Cephalosporin derviatives

ABSTRACT

Novel cephem derivatives represented by the general formula ##STR1## in which the Acyl substituent is a group of the formula ##STR2## wherein Ar is a lipophilic optionally substituted phenyl, naphthyl or pyridyl group; R 1  represents either the residue of a heterocyclic amino acid or a C 2  -C 10  alkyl group substituted by both a carboxyl group and a group of the formula --NR 9  R 10  or ##STR3## in which R 9  and R 10  are each independently hydrogen or C 1  -C 6  alkyl, said C 2  -C 10  alkyl group being optionally interrupted by one or more nitrogen atoms or carbonyl groups, and R 2  and R 3  are each independently hydrogen, alkyl or aminoalkyl are gram-positive antibacterial agents, especially useful in the treatment of diseases caused by methicillin-resistant Staphylococcus aureus (also referred to below as MRSA or methicillin-resistant S. aureus).

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to new cephem derivatives representedby the general formula ##STR4## in which the Acyl substituent is a groupof the formula ##STR5## where Ar is an optionally substituted lipophilicphenyl, naphthyl or pyridyl group, R¹ represents either the residue of aheterocyclic amino acid or a C₂ -C₁₀ alkyl group substituted by both acarboxyl or sulfonyl group and a group of the formula --NR⁹ R¹⁰ or##STR6## in which R⁹ and R¹⁰ are each independently hydrogen or C₁ -C₆alkyl, said C₂ -C₁₀ alkyl group being optionally interrupted by one ormore nitrogen atoms or carbonyl groups, and R² and R³ are eachindependently hydrogen, alkyl or aminoalkyl. The derivatives aregram-positive antibacterial agents, especially useful in the treatmentof diseases caused by methicillin-resistant Staphylococcus aureus (alsoreferred to below as MRSA or methicillin-resistant S. aureus).

2. Description of the Prior Art

The literature discloses a vast number of cephem derivatives having awide variety of C-3 and C-7 substituents. Applicants are not aware,however, of any literature disclosing compounds with the combination ofC-3 and C-7 substituents found by applicants to give good activityagainst MRSA organisms. There are, however, references which disclosecephalosporins having the type of 7-substituents or the type of3-substituents present in the compounds claimed in the presentapplication.

For example, there are references which disclose applicants' C-7substituents. Among such references disclosing 7-substituents of thetype ##STR7## where Ar is an aromatic group are the following:

U.S. Pat. No. 4,056,676 discloses cephem derivatives of the generalformula ##STR8## where Z is hydrogen or fluorine; and when Z ishydrogen, each of X and Y is hydrogen or chlorine selected so that thephenyl ring is substituted with 1 or 2 chlorine atoms and so that whenone chlorine atom is present said chlorine atom is in the 3-position,and when two chlorine atoms are present said chlorine atoms are in the3,4-, the 3,5- or the 2,5-positions; and when Z is fluorine, saidfluorine is in the 3- or 4-positions of the phenyl ring and each of Xand Y is hydrogen or chlorine selected so that when the phenyl ring issubstituted with 1 or 2 chlorine atoms, one of the chlorine atoms is inthe 3- or 4-position of the phenyl ring; R¹ is hydrogen,dicyclohexylamine, or a pharmaceutically acceptable cation; and R is,inter alia, N-pyridino. Among the compounds specifically disclosed arethose of the formulae: ##STR9## The compounds disclosed are said to beuseful for treating and inhibiting the growth of MRSA organisms.

The cephalosporin derivative of the formula ##STR10## is disclosed inAntimicrobial Agents and Chemotherapy--1966, pg. 573-580 at page 576(Compound No. 48).

J. Antibiotics, 26(12), 737-744, 1973, discloses the compound of theformula ##STR11##

U.K. Patent 998,265 discloses cephem derivatives of the general formula##STR12## in which R¹, taken alone, is --OH, C₁ -C₈ acyloxy, ortertiaryamino, R² is --OH when R¹ is --OH, R² is --OH when R¹ is C₁ -C₈acyloxy, R² is --O-- when R¹ is tertiaryamino, R¹ and R², when takentogether, are --O--, R³ and R⁴ represent hydrogen, alkyl radicals havingfrom 1 to 6 carbon atoms, alkenyl radicals having from 2 to 6 carbonatoms, cycloalkyl radicals having from 5 to 7 carbon atoms, oralkoxyalkyl radicals having from 2 to 6 carbon atoms; n represents 0 to4; and R⁵ represents an alkyl radical having from 1 to 6 carbon atoms,an alkenyl or alkynyl radical having from 2 to 6 carbon atoms, acycloalkyl radical having 5 or 6 carbon atoms, phenyl, β-furyl,β-thienyl, thienyl, or naphthyl, or a fluoro, chloro, bromo, nitro,trifluoromethyl, C₁ -C₄ alkyl, C₁ -C₄ alkylmercapto, or C₁ -C₄ alkoxysubstitution product of such radicals.

U.K. Published Application No. 2,007,221 A discloses cephalosporinderivatives of the formula ##STR13## wherein Y is hydrogen, chlorine,bromine, C₁ -C₄ alkyl or C₁ -C₄ alkoxy; Z is a bond, oxygen or sulfur; Wis hydrogen, methyl, amino, hydroxy, SO₃ H or COOR₄ wherein R₄ ishydrogen or 5-indanyl with the proviso that when Z is oxygen or sulfur,W is other than hydroxy; R₁ is hydrogen or methoxy; R₂ is hydrogen,acetoxy, 1,3,4-thiadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio,tetrazol-5-ylthio, 1-methyltetrazol-5-ylthio, 1,3,4-oxadiazol-2-ylthio,5-methyl-1,3,4-oxadiazol-2-ylthio, 1,3,4-triazol-2-ylthio,5-methyl-1,3,4-triazol-2-ylthio, 1,2,3-triazol-5-ylthio, pyridinium or4-aminocarbonylpyridinium; R₃ is hydrogen, a negative charge when R₂ ispyridinium or 4-aminocarbonylpyridinium, a cation of an alkali metal oran alkaline earth metal, ammonium or organic ammonium cations, C₁ -C₄alkyl, (C₂ -C₅ alkanoyloxy)methyl, (C₂ -C₅) alkanoylamino)methyl, [C₂-C₅ alkanoyl(C₁ -C₄ alkoxy)carbonyl(C₁ -C₄ alkyl)-amino-methyl, p-(C₂-alkanoyloxy)benzylamino(C₂ -C₁₅ alkanoyloxy)methyl, (C₁ -C₄alkyl)amino(C₂ -C₁₅ alkanoyloxy)methyl or di(C₁ -C₄ alkyl)amino(C₂ -C₁₅alkanoyloxy)methyl; and pharmaceutically acceptable salts thereof.

U.S. Pat. No. 3,217,000 discloses cephem derivatives of the formula##STR14## wherein Thi is 2-thienyl or 3-thienyl and R is a substituentat the 3 or 4 position of the pyridino ring selected from the groupconsisting of cyano, carboxy, carbamyl, N-methylcarbamyl, carbo(C₁ -C₄alkoxy), hydroxy and (C₁ -C₄)alkanoyl; and the salts thereof withpharmaceutically acceptable acids.

There is also literature disclosing cephalosporins having 3-substituentsof the type ##STR15## where R is an optionally substituted aliphatic oraromatic group. Among such references are those of the following:

U.S. Pat. No. 4,758,557 discloses cephalosporin derivatives of thegeneral formula ##STR16## wherein A represents an alkanoyloxy grouphaving 2-5 carbon atoms; a carbamoyloxy group; an azido group; or anunsubstituted or substituted pyridylthio group of the formula ##STR17##where n is 0 or an integer of 3-5; R¹ and R² may be the same ordifferent and each represents a hydrogen atom, a halogen atom, acarboxyl group or an optionally halogen-substituted lower-alkyl grouphaving 1-5 carbon atoms; or an unsubstituted or substitutedpyridiniumthio group of the formula ##STR18## where n, R¹ and R² havethe same meanings as above; R³ represents a linear or branched-chainalkyl group having 1-5 carbon atoms, a halogen-substituted alkyl group,a cyclopropyl group, a cyclopropylmethyl group, an alkenyl group, anoxygen atom or a group of (--CH₂)_(m) --B where m is an integer of 0-3and B represents a hydroxyl group, an alkoxy group, an amino group, analkyl-substituted amino group, a carboxyl group, a carbamoyl group, asulfonic acid group, a sulfonic acid amide group, a hydroxamic group, acyano group, a thiol group, an alkylthio group, amethanesulfonylaminocarbonyl group or an acetamidosulfonyl group; or anunsubstituted or substituted pyridinium group of the formula ##STR19##where n has the same meaning as above; R⁴ and R⁵ may be the same ordifferent and each represent a hydrogen atom, a linear or branched alkylgroup having 1-5 carbon atoms, a carboxyl group, a carbamoyl group, asulfonic acid group, a sulfonic acid amide group, a linear or branchedalkylthio group having 1-5 carbon atoms, a halogen-substituted alkylthiogroup, a cycloalkanothio group, a carbamoylalkylthio group, analkoxyalkylthio group or an alkyl-substituted aminoalkylthio group; or a5- or 6-membered heterocyclicthio or bicycloheterocyclicthio group ofthe formula

    --S--Het

wherein Het represents an optionally substituted thiazole, isothiazole,1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,3,4-triazole, 1,2,3,4-tetrazole,pyrimidine, 1,2,4-triazine, benzothiazole, benzimidazole, benzoxazole,1,3,4-triazaindolidine or 2,3-dihydro-1H-indolidinium group.

Illustrative of the compounds encompassed by U.S. Pat. No. 4,758,557 isMT0703 having the structure ##STR20## which is disclosed in J.Antibiotics 43(2), 189-198, 1990.

U.S. Pat. No. 4,786,633 discloses cephalosporin derivatives of theformula ##STR21## wherein R² is a substituted or unsubstitutedheterocyclic group having 1-3 hetero atoms selected from the groupconsisting of nitrogen and sulfur. The R² group may be, for example, agroup of the formula ##STR22## where R⁴ is lower alkenyl, lower alkyl,or a lower alkyl group substituted with a carbamoyl group and R⁵ and R⁶are the same or different and each represent hydrogen or lower alkyl.

Published European Patent Application 409,164 A2 discloses cephalosporinderivatives of the formula ##STR23## wherein R¹ is an amino group oracylamino; R² is hydrogen or methoxy; R³ is hydrogen or a mono- ordivalent substituent; R⁴ is optionally protected vic-dihydroxyaryl; R⁵is straight or branched lower alkylene; R⁶ is hydrogen, acarboxy-protecting group or a negative charge when combined with Y; X isoxygen, sulfur, or sulfinyl; and Y is an anion or a negative charge whencombined with R⁶ ; and the dotted line shows the presence or absence ofa bond.

SUMMARY OF THE INVENTION

The present invention provides a novel series of cephem derivatives ofthe general formula ##STR24## wherein Ar is a group selected from##STR25## in which R⁴, R⁵ and R⁶ are each independently hydrogen,halogen, trihalomethyl, nitro, amino, hydroxy, hydroxy(C₁ -C₆) alkyl, C₁-C₆ alkyl, --(CH₂)_(n) OR⁷ or --(CH₂)_(n) SR⁷ ; n is an integer of from1 to 6; R⁷ is hydrogen or C₁ -C₆ alkyl; R¹ is selected from the groupconsisting of

(a) a C₂ -C₁₀ alkyl group substituted by a carboxyl or sulfonyl groupand a group of the formula ##STR26## in which R⁹ and R¹⁰ are eachindependently hydrogen or C₁ -C₆ alkyl, said C₂ -C₁₀ alkyl group beingoptionally interrupted by one or more nitrogen atoms or carbonyl groups;and

(b) a heterocyclic amino acid group of the formula ##STR27## R² and R³are each independently hydrogen, C₁ -C₆ alkyl or amino(C₁ -C₆)alkyl; andR¹¹ is hydrogen, an anionic charge or a carboxyl-protecting group,provided that when R¹¹ is hydrogen or a protecting group, there is alsopresent a counter ion; or a pharmaceutically acceptable salt or prodrugthereof. The compounds of formula I are antibacterial agents useful inthe treatment of infections in humans and other animals caused by avariety of gram-positive bacteria, particularly methicillin-resistant S.aureus.

Also included in the invention are processes for preparing the compoundsof formula I and pharmaceutical compositions containing said compoundsin combination with pharmaceutically acceptable carriers or diluents.

DETAILED DESCRIPTION

The present invention provides novel cephem derivatives of generalformula I above which are antibacterial agents useful in the treatmentof infectious diseases in humans and other animals. The compoundsexhibit good activity against a variety of gram-positive microorganisms,e.g. S. pneumoniae, S. pyrogenes, S. aureus, E. faecalis, E. facecium,S. epidermidis and S. hermolyticus, and are particularly useful againststrains of methicillin-resistant S. aureus.

The compounds of formula I are characterized by a substitutedpyridiniumthiomethyl group of the type ##STR28## at the 3-position ofthe cephem ring and a lipophilic 7-substituent of the type ##STR29##wherein Ar is an aromatic group selected from optionally substitutedphenyl, naphthyl or pyridyl. To elaborate on the definitions for thesubstituents of the formula I compounds:

(a) "Halogen" includes chloro, bromo, fluoro and iodo, and is preferablychloro or bromo;

(b) "Trihalomethyl" includes trichloromethyl, trifluoromethyl,tribromomethyl and triiodomethyl, but is preferably trifiuoromethyl;

(c) The aliphatic "alkyl", "alkoxy", "alkenyl" and "alkynyl" groups maybe straight or branched-chains having the specified number of carbonatoms, e.g., in the case of C₁ -C₁₀ alkyl, the alkyl group may have from1 to 10 carbon atoms. It is preferred that the groups have up to 6carbon atoms and most preferably up to 4 carbon atoms.

The term "pharmaceutically acceptable salt" as used herein is intendedto include the nontoxic acid addition salts with inorganic or organicacids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric,maleic, acetic, citric, succinic, benzoic, fumaric, mandelic,p-toluenesulfonic, methanesulfonic, ascorbic, lactic, gluconic,trifluoroacetic, hydroiodic, hydrobromic, and the like. Some of thecompounds of the present invention have an acidic hydrogen and can,therefore, be converted with bases in a conventional manner intopharmaceutically acceptable salts. Such salts, e.g. ammonium, alkalimetal salts, particularly sodium or potassium, alkaline earth metalsalts, particularly calcium or magnesium, and salts with suitableorganic bases such as lower alkylamines (methylamine, ethylamine,cyclohexylamine, and the like) or with substituted lower alkylamines(e.g. hydroxyl-substituted alkylamines such as diethanolamine,triethanolamine or tris-(hydroxymethyl) aminomethane), or with basessuch as piperidine or morpholine, are also intended to be encompassed bythe term "pharmaceutically acceptable salt".

Compounds of formula I in the form of acid addition salts may be writtenas ##STR30## where x.sup.⊖ represents the acid anion and R¹¹ is hydrogenor a carboxyl-protecting group. The counter anion x.sup.⊖ may beselected so as to provide pharmaceutically acceptable salts fortherapeutic administration.

The carboxyl-protecting group R¹¹ is intended to include readilyremovable ester groups which have been employed to block a carboxylgroup during the reaction steps used to prepare compounds I and whichcan be removed by methods which do not result in any appreciabledestruction of the remaining portion of the molecule, e.g. by chemicalor enzymatic hydrolysis, treatment with chemical reducing agents undermild conditions, irradiation with ultraviolet light or catalytichydrogenation, etc. Examples of such protecting groups includebenzhydryl, p-nitrobenzyl, 2-naphthylmethyl, allyl, benzyl,p-methoxybenzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl,acetonyl, o-nitrobenzyl, 4-pyridylmethyl and C₁ -C₆ alkyl such asmethyl, ethyl or t-butyl. Included within such protecting groups arethose which are hydrolyzed under physiological conditions such aspivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, α-acetoxyethyl,α-pivaloyloxyethyl, and methoxymethyl. Compounds of formula I with suchphysiologically hydrolyzable carboxyl protecting groups are alsoreferred to herein and in the claims as "prodrugs". Compounds of formulaI where R¹¹ is a physiologically removable protecting group are usefuldirectly as antibacterial agents. Compounds where an R¹¹ protectinggroup is not physiologically removable are useful intermediates whichcan be easily converted to the active form by conventional deblockingprocedures well-known to those skilled in the art.

Compounds of formula I wherein a hydroxyl substituent is esterified witha group hydrolyzable under physiological conditions are also includedwithin the scope of the term "prodrug" as used herein and in the claims.Such hydroxyl protecting groups may be employed, for example, toincrease the solubility of the formula I compound. Illustrative ofsuitable ester "prodrugs" of this type are compounds of formula Iwherein one or more hydroxy substituent groups are converted to sulfate(--OSO₃ H) or phosphate (--OPO₃ H₂) groups.

A preferred embodiment of the present invention comprises compounds offormula I wherein Ar is ##STR31## in which R⁴, R⁵ and R⁶ are eachindependently hydrogen, halogen, C₁ -C₆ alkyl, trifiuoromethyl, hydroxy,hydroxymethyl or amino.

Another preferred embodiment of the present invention comprisescompounds of formula I wherein Ar is a group selected from ##STR32## inwhich R⁴, R⁵ and R⁶ are each independently hydrogen, halogen,trihalomethyl, nitro, amino, hydroxy, hydroxy(C₁ -C₆) alkyl, C₁ -C₆alkyl, --(CH₂)_(n) OR⁷ or --(CH₂)_(n) SR⁷ ; n is an integer of from 1 to6; R⁷ is hydrogen or C₁ -C₆ alkyl; R¹ is selected from the groupconsisting of ##STR33## wherein R⁸ is NR⁹ R¹⁰ or ##STR34## in which R⁹and R¹⁰ are each independently hydrogen or C₁ -C₆ alkyl; m is 0 or 1; nis as defined above; o is 0 or an integer of from 1 to 4; p is 0 or 1; qis 0 or 1, with the proviso that q is 0 only when p is 0; r and s eachrepresent an integer of from 1 to 4; R¹² is C₁ -C₆ alkyl; R² and R³ areeach independently hydrogen, C₁ -C₆ alkyl or amino(C₁ -C₆)alkyl; and R¹¹is hydrogen, an anionic charge or a carboxyl-protecting group, providedthat when R¹¹ is hydrogen or a protecting group, there is also present acounter ion; or a pharmaceutically acceptable salt or prodrug thereof.

Within this group, the preferred compounds are those wherein Ar is##STR35## in which R⁴, R⁵ and R⁶ are each independently hydrogen,halogen, C₁ -C₆ alkyl, trifluoromethyl, hydroxy, hydroxymethyl or amino.

The preferred individual compounds of the present invention, all ofwhich have an MIC vs a representative MRSA strain of ≧8 μg/ml, arelisted below:

1[(5S)-5-Amino-5-carboxy-1-pentyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 3)

1-[(5S)-5-Amino-5-carboxy-1-pentyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 4)

1-[(±)-5-Amino-5-carboxy-1-hexyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 5)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 6)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 7)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 8)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3,5-dichloro-4-hydroxyphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 9)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-chloro-5-trifluoromethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 10)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3,5-dichloro-4-aminophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 11)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dimethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 12)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 13)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 14)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 15)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-hydroxymethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 16)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-fluorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 17)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 18)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-chloro-5-trifluoromethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 19)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 20)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,3-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 21)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2-ethyl-4-[[(6R)-trans-2-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 22)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2-methyl-4-[[(6R)-trans-2-carboxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 23)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2-(3-aminopropyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 24)

1-[(4R)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 25)

1-[(4R)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-hydroxymethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 26)

1-[(4R)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 27)

1-[(3S)-3-Amino-3-carboxy-1-propyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 28)

1-[(2R)-2-Amino-2-carboxy-1-ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 29)

1-[(2S)-5-Amino-2-carboxy-1-pentyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 30)

1-[(2S)-4-Amino-2-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenyl)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 31)

1-[(2S)-4-Guanidino-2-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 32)

1-[(2S,4R)-2-Carboxy-4-pyrrolidinyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 33)

1-[(1S)-1-(3-Amino-1-propyl)-N-(carboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 2)

1-[(1S)-1-(3-Guanidino-1-propyl)-N-(carboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 34)

1-[N-((1S)-1-carboxy-4-guanidino-1-butyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 35)

1-[(5S)-5-Amino-5-(N-carboxymethyl)carbamoyl-1-pentyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 36)

1-[(4S)-4-Amino-4-(N-carboxymethyl)carbamoyl-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 37)

1-[N-(Carboxymethyl)-N-(2-amino-1-ethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 38)

1-[N-(Carboxymethyl)-N-(3-amino-1-propyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 1)

1-[N-(Carboxymethyl)-N-(2-guanidino-1-ethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 39)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-iodophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 40)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-chlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 41)

1-[(4R)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-iodophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 42)

1-[(4S)-4-Guanidino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 43)

1-[(4S)-4-(t-Butoxycarbonylamino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-iodophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 44)

1-[(2S,4S)-2-Carboxypyrrolidin-4-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 45)

The more preferred individual compounds of the present invention, all ofwhich have a MIC≦8 μg/mL and a PD₅₀ ≦5 mg/kg against a representativestrain of MRSA, are listed below:

1-[(5S)-5-Amino-5-carboxy-1-pentyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 3)

1-[(5S)-5-Amino-5-carboxy-1-pentyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 4)

1-[(±)-5-Amino-5-carboxy-1-hexyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 5)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 6)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 7)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 8)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-chloro-5-trifluoromethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 10)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3,5-dichloro-4-aminophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 11)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 14)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 15)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-hydroxymethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 16)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 18)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-chloro-5-trifluoromethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 19)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 20)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,3-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 21)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2-ethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 22)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2-methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 23)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2-(3-aminopropyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 24)

1-[(4R)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 25)

1-[(4R)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-hydroxymethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 26)

1-[(4R)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 27)

1-[(2S)-5-Amino-2-carboxy-1-pentyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 30)

1-[(2S)-4-Amino-2-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 31)

1-[(2S)-4-Guanidino-2-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 32)

1-[(2S,4R)-2-carboxypyrrolidin-4-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 33)

1-[(1S)-1-(3-Amino-1-propyl)-N-(carboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 2)

1-[(1S)-1-(3-Guanidino-1-propyl)-N-(carboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 34)

1-[N-((1S)-1-Carboxy-4-guanidino-1-butyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 35)

1-[(5S)-5-Amino-5-(N-carboxymethyl)carbamoyl-1-pentyl]-4-[[((6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 36)

1-[(4S)-4-Amino-4-(N-carboxymethyl)carbamoyl-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 37)

1-[N-(Carboxymethyl)-N-(2-amino-1-ethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 38)

1-[N-(Carboxymethyl)-N-(3-amino-1-propyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 1)

1-[(4S)-4-Guanidino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7[(2,5-dichlorophenylthioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3yl]methylthio]pyridinium inner salt or a pharmaceutically acceptablesalt thereof (compound of Example 43)

The most preferred individual compounds of the present invention arelisted below:

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 6)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 7)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 8)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 14)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 18)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-carboxy-8-oxo-7-[(2-chloro-5-trifluoromethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 19)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 20)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,3-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 21)

1-[(4S)-4-Amino-4-carboxy-1-butyl]-2-methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 23)

1-[(4R)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 25)

1-[(4R)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-hydroxymethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 26)

1-[(2S)-4-Amino-2-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 31)

1-[(2S)-4-Guanidino-2-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 32)

1-[(1S)-1-(3-Amino-1-propyl)-N-(carboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 2)

1-[N-((1S)-1-carboxy-4-guanidino-1-butyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 35)

1-[(5S)-5-Amino-5-(N-carboxymethyl)carbamoyl-1-pentyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 36)

1-[N-(Carboxymethyl)-N-(3-amino-1-propyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 1)

The compounds of the present invention can be made by conventionalmethods. Two suitable procedures are summarized by the followingreaction scheme: ##STR36##

To elaborate on the above process, thiol VII is converted into thearylthioacetic acid derivative VI by treatment with bromoacetic acidunder basic conditions (e.g. aqueous sodium or potassium hydroxide). Thereaction temperature for this step is typically between 20° C. and 100°C. Starting thiol VII is commercially available or can be preparedaccording to known literature procedures. Following acidification of thereaction mixture, the product VI is typically isolated bycrystallization or, if necessary, it can be purified by chromatography.

Arylthioacetic acid VI is then coupled with a suitable cephemintermediate having a 3-substituent leaving group. For example, theleaving group may be acetoxy or halo. In the preferred embodimentillustrated by the reaction scheme, the cephem intermediate is the3-chloro cephem V, but other suitable cephem intermediates withequivalent leaving groups at the 3-position could also be employed. Thecephem intermediate V may be acylated with VI or a reactive derivativethereof by conventional acylation procedures well-known in thecephalosporin art to give N-acylated intermediate IV. In addition tousing the free arylthioacetic acid, e.g. with a suitable condensingagent such as dicyclohexylcarbodiimide, acylating agent VI may also beemployed in the form of equivalent acylating derivatives such as an acidanhydride, mixed anhydride, activated ester, or acid halide. The cephemintermediate preferably has the carboxyl group protected by aconventional carboxyl-protecting group which can be readily removed.Examples of such protecting groups are discussed above and includebenzyl, 4-nitrobenzyl, 4-methoxybenzyl, diphenylmethyl, allyl, and thelike. Other examples of suitable protecting groups are disclosed inProtective Groups in Organic Synthesis, Theodora W. Greene (John Wiley &Sons, 1981), Chapter 5. In one embodiment, intermediate V may beacylated with acid VI in the presence of dicyclohexylcarbodiimide and inan inert solvent such as tetrahydrofuran or dichloromethane. Thereaction temperature is typically between -20° C and 50° C. Uponcompletion of the reaction, insoluble material is removed by filtration,the filtrate is concentrated, and the residue is treated with arelatively non-polar solvent such as diethyl ether or ethyl acetateresulting in precipitation of the desired product. Alternatively, acidVI may be converted to the corresponding acid chloride, for example bytreatment with thionyl chloride with or without a solvent such asdichloromethane, followed by coupling with cephem amine V in thepresence of a base such as triethylamine or N-methylmorpholine to giveintermediate IV. Cephem IV is typically isolated after aqueous work-upand evaporation of volatile solvents followed by trituration of thecompound with a relatively non-polar solvent such as diethyl ether orethyl acetate. This intermediate may be used in the next reaction stepas the X=chloride derivative, or can be converted to the X=bromide orX=iodide derivative by treatment with the appropriate metal halide in asolvent such as acetone.

Conversion of cephem IV to the target quaternary cephems I isaccomplished by two different methods. One method for preparation of Ientails displacement of an appropriate 3-substituent leaving group with4-mercaptopyridine followed by quaternization of the pyridyl nitrogen,and then deprotection of the cephem carboxylate ester. For example,cephera IV (X=Cl) is treated with optionally substituted4-mercaptopyridine and sodium iodide in a one-pot reaction to giveintermediate II. Reaction of thiopyridyl derivative II with a reactivealkylating agent provides the quaternary cephem intermediate I'.Examples of alkylating agents are α-halocarbonyl derivatives such asN-substituted haloacetamides. The alkylation reaction is carried out inan inert solvent such as acetone, dimethylformamide, or tetrahydrofuranand is run at temperatures between -20° C and 100° C. Removal of thecephera carboxylate ester protecting group to give I is thenaccomplished under acidic conditions. For example, when R isdiphenylmethyl or 4-methoxybenzyl, I is obtained upon treatment of I'with trifluoroacetic acid neat or in an inert solvent such as methylenechloride. A reagent such as anisole may also be employed to scavenge theliberated ester protecting group. The reaction temperature is usually ator below room temperature. The deprotection may also be carried out bytreatment with other protic acids such as hydrochloric acid in a solventsuch as methanol. The final product is typically isolated byprecipitation or crystallization. In some cases, cephem I is purified bycolumn chromatography, for example on reversed-phase adsorbent.

In a second method of preparing quaternary cephems I, intermediate IV isdeprotected under acidic conditions, followed by reaction of theresulting intermediate IV' with a thiopyridone derivative III. Forexample, when R is diphenylmethyl or 4-methoxybenzyl, cephem acid IV' isobtained upon treatment of IV with trifluoroacetic acid neat or in aninert solvent such as methylene chloride. A reagent such as anisole mayalso be employed to scavenge the liberated ester protecting group. Thereaction temperature is usually at or below room temperature. Thedeprotection may also be carried out by treatment with other proticacids such as hydrochloric acid in a solvent such as methanol. The finalproduct is typically isolated by precipitation or crystallization.Reaction of IV' with a thiopyridone derivative III in a solvent such asdimethylformamide, dimethyl sulfoxide, ethanol, methanol, or otherappropriate solvents at a temperature between -20° C. and 100° C.affords target quaternary cephem I. The final product is isolated asdescribed above. Thiopyridones III are typically prepared according to amethod analogous to that described in T. Takahashi et al., EuropeanPatent Application No. 209751 and in I. E. El-Kholy et al., J.Heterocyclic Chem. Vol. 11, p. 487 (1974). This procedure entailsreaction of 4-thiopyrone (European Patent No. 209751) with anappropriate primary amine in a solvent such as aqueous methanol orethanol at a temperature ranging between 0° C. and 78° C. The primaryamine may be in the form of a zwitterion in examples where there is afree acid group present in the molecule. In these cases, a base such assodium hydroxide, sodium bicarbonate, or pyridine is added to form thefree amine in situ. The product may be isolated as its sodium salt byevaporation of volatile solvents, followed by trituration with a solventsuch as diethyl ether or ethyl acetate. Alternatively, the reactionmixture may be acidified and extracted with an organic solvent to affordthe product as the free carboxylic acid. If the carboxylate group isprotected as an ester, the amine may be free or present as an acid salt.In the latter case, a base such as sodium hydroxide, sodium bicarbonate,or pyridine is added to form the free amine in situ. The product istypically isolated by precipitation or by reversed phase columnchromatography following removal of volatile solvents.

The thiopyridone derivatives of formula III are novel compounds and areanother aspect of the present invention. The preferred R¹, R², and R³substituents of derivatives III are as disclosed above in connectionwith the end-products of formula I.

It will be understood that where the substituent groups used in theabove reactions contain certain reaction-sensitive functional groupssuch as amino or carboxylate groups which might result in undesirableside-reactions, such groups may be protected by conventional protectinggroups known to those skilled in the art. For example, thiopyridoneintermediates of formula III may have an amine functional groupprotected as the t-butyloxycarbamate. Suitable protecting groups andmethods for their removal are illustrated, for example, in ProtectiveGroups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons,1991). It is intended that such "protected" intermediates andend-products are included within the scope of the present disclosure andclaims.

The desired end-product of formula I may be recovered either as thezwitterion or in the form of a pharmaceutically acceptable acid additionsalt, e.g. by addition of the appropriate acid such as HCl, HI ormethanesulfonic acid to the zwitterion. Compounds of formula I where R¹¹is hydrogen or an anionic charge, or a pharmaceutically acceptable saltthereof, may be converted by conventional procedures to a correspondingcompound where R¹¹ is a physiologically hydrolyzable ester group.

It will be appreciated that certain products within the scope of formulaI may have a C-3 substituent group which can result in formation ofoptical isomers. It is intended that the present invention includewithin its scope all such optical isomers as well as epimeric mixturesthereof, i.e. R- or S- or racemic forms.

The novel cephalosporin derivatives of general formula I wherein R¹¹ ishydrogen, an anionic charge or a physiologically hydrolyzablecarboxyl-protecting group, or the pharmaceutically acceptable salts orprodrugs thereof, are potent antibiotics active against manygram-positive bacteria. While they may be used, for example, as animalfeed additives for promotion of growth, as preservatives for food, asbactericides in industrial applications, for example in waterbased paintand in the white water of paper mills to inhibit the growth of harmfulbacteria, and as disinfectants for destroying or inhibiting the growthof harmful bacteria on medical and dental equipment, they are especiallyuseful in the treatment of infectious disease in humans and otheranimals caused by the gram-positive bacteria sensitive to the newderivatives. Because of their excellent activity against MRSA organisms,they are particularly useful in the treatment of infections resultingfrom such bacteria.

The pharmaceutically active compounds of this invention may be usedalone or formulated as pharmaceutical compositions comprising, inaddition to the active cephem ingredient, a pharmaceutically acceptablecarrier or diluent. The compounds may be administered by a variety ofmeans, for example, orally, topically or parenterally (intravenous orintramuscular injection). The pharmaceutical compositions may be insolid form such as capsules, tablets, powders, etc. or in liquid formsuch as solutions, suspensions or emulsions. Compositions for injection,the preferred route of delivery, may be prepared in unit dose form inampules or in multidose containers and may contain additives such assuspending, stabilizing and dispersing agents. The compositions may bein ready- to-use form or in powder form for reconstitution at the timeof delivery with a suitable vehicle such as sterile water.

The dosage to be administered depends, to a large extent, on theparticular compound being used, the particular composition formulated,the route of administration, the nature and condition of the host andthe particular situs and organism being treated. Selection of theparticular preferred dosage and route of application, then, is left tothe discretion of the physician or veterinarian. In general, however,the compounds may be administered parenterally or orally to mammalianhosts in an amount of from about 50 mg/day to about 20 g/day.Administration is generally carried out in divided doses, e.g., three tofour times a day, analogous to dosing with a cephalosporin such ascefotaxime.

To illustrate the antibacterial properties of the compounds of thepresent invention, the following biological data is presented below.

IN VITRO ACTIVITY

Samples of the compounds prepared below in Examples 1-45 after solutionin water and dilution with Nutrient Broth were found to exhibit thefollowing ranges of Minimum Inhibitory Concentrations (MIC) versus theindicated microorganisms as determined by tube dilution. The MICs weredetermined using a broth micro dilution assay in accordance with thatrecommended by the National Committee for Clinical Laboratory Standards(NCCLS). Mueller-Hinton medium was used except for Streptococci whichwas tested in Todd Hewitt broth. The final bacterial inoculate containedapproximately 5×10⁵ cfu/ml and the plates were incubated at 35° C. for18 hours in ambient air (Streptococci in 5% CO₂). The MIC was defined asthe lowest drug concentration that prevented visible growth.

    ______________________________________                                                               MIC                                                    Microorganism          range in mcg/ml                                        ______________________________________                                        S. aureus methicillin resistant A27223                                                               1-8                                                    S. Pneumoniae A9585    0.001-0.06                                             S. pyogenes A9604      0.0005-0.06                                            E. faecalis A20688     0.125-4                                                E. faecium A24885      0.5-16                                                 S. aureus A9537, penicillinase negative                                                              0.001-0.06                                             S. aureus A15090, penicillinase positive                                                             0.125-0.5                                              S. epidermidis A24548  0.007-0.25                                             S. epidermidis A25783, methicillin resistant                                                         0.06-0.5                                               S. hemolyticus A21638  0.015-0.25                                             S. hemolyticus A27235, methicillin resistant                                                         0.5-8                                                  ______________________________________                                    

IN VIVO ACTIVITY

The in vivo therapeutic efficacy of the compounds prepared in Examples1-39 below after intramuscular injection to mice experimentally infectedwith the representative MRSA strain A27223 was also measured.

The determination of the effectiveness of antimicrobial agents inStaphylococcus aureus systemic infection in mice

Organisms: The test organism, MRSA strain A27223 used to generatesystemic infection in mice, is grown on two large Brain Heart InfusionAgar plates. On each plate, 0.5 ml of frozen stock culture is platedout. Plates are then incubated for 18 hours at 30° C. The next day eachplate is washed with 20 ml of Brain Heart Infusion Broth and then pooledtogether. A microscopic direct count of microorganism is done using a1:1000 dilution of plate wash. After a direct count is obtained, thenumber of organisms per milliliter is calculated. The count is adjustedto the desired amount of inoculum by diluting in 4% hog mucin. Thedesired challenge (amount of organisms given to mice) is 2.4×10⁸ cfu/0.5ml/mouse for MRSA strain A27223. The mice are infected intraperitoneallywith 0.5 ml of challenge. Ten non-treated infected mice are used ascontrols.

Mice: Mice used are male ICR mice. The average weight of the animals isfrom 20 to 26 grams.

Drug preparation and treatment: Compounds are tested at 4 dose levels,(25, 6.25, 1.56, and 0.39 mg/kg) and prepared in 5% cremophor, unlessotherwise specified. Vancomycin is used as the control compound, and isdosed at 6.25, 1.56, 0.39, and 0.098 mg/kg. It is prepared in 0.1Mphosphate buffer. There are five infected mice per dose level, and theyare treated with 0.2 ml of the test compound, preferably byintramuscular injection. Treatment begins 15 minutes and 2 hourspost-infection.

Test duration: A PD₅₀ (the dose of drug given which protects 50% of micefrom mortality) runs for 5 days. During this time, mortality of mice arechecked every day and deaths are recorded. The cumulative mortality ateach dose level is used to calculate a PD₅₀ value for each compound.Surviving mice are sacrificed at the end of day 5 by CO₂ inhalation.

Calculation: Actual calculation of PD₅₀ is performed with a computerprogram using the Spearman-Karber procedure.

Result: The in vivo efficacy, expressed as the PD₅₀ value, ranged fromabout 1 to 22 mg/kg (for certain compounds, more than one test wascarried out; the indicated range is for at least one test result whenmultiple tests were done).

ILLUSTRATIVE EXAMPLES

The following examples illustrate the invention, but are not intended asa limitation thereof. The abbreviations used in the examples areconventional abbreviations well-known to those skilled in the art. Someof the abbreviations used are as follows:

h=hour(s)

mol=mole(s)

mmol=mmole(s)

g=gram(s)

THF=tetrahydrofuran

L=liter(s)

mL=milliliter(s)

Et₂ O=diethyl ether

EtOAc=ethyl acetate

MeOH=methanol

DMF=dimethylformamide

In the following examples, all temperatures are given in degreesCentigrade. Melting points were determined on an electrothermalapparatus and are not corrected. Proton and carbon-13 nuclear magneticresonance (¹ H and ¹³ C NMR) spectra were recorded on a Bruker AM-300 ora Varian Gemini 300 spectrometer. All spectra were determined in CDCl₃,DMSO-d₆, CD₃ OD, or D₂ O unless otherwise indicated. Chemical shifts arereported in δ units relative to tetramethylsilane (TMS) or a referencesolvent peak and interproton coupling constants are reported in Hertz(Hz). Splitting patterns are designated as follows: s, singlet; d,doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; dd,doublet of doublets; dt, doublet of triplets; and app d, apparentdoublet, etc. Infrared spectra were determined on a Perkin-Elmer 1800FT-IR spectrometer from 4000 cm⁻¹ to 400 cm⁻¹, calibrated to 1601 cm⁻¹absorption of a polystyrene film, and are reported in reciprocalcentimeters (cm⁻¹). Mass spectra were recorded on a Kratos MS-50 or aFinnegan 4500 instrument utilizing direct chemical ionization (DCI,isobutene), fast atom bombardment (FAB), or electron ion spray (ESI).Ultraviolet spectra were determined on a Hewlett Packard 8452 diodearray spectrophotometer in the solvent indicated.

Analytical thin-layer chromatography (TLC) was carried out on precoatedsilica gel plates (60F-254) and visualized using UV light, iodinevapors, and/or staining by heating with methanolic phosphomolybdic acid.Column chromatography, also referred to as flash chromatography, wasperformed in a glass column using finely divided silica gel at pressuressomewhat above atmospheric pressure with the indicated solvents.Reversed-phase analytical thin-layer chromatography was carried out onprecoated reverse phase plates and visualized using UV light or iodinevapors. Reversed-phase column chromatography was performed in a glasscolumn using Baker Octadecyl (C₁₈), 40 μm.

EXAMPLE 1

1-[N-(Carboxymethyl)-N-(3-amino-1-propyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt ##STR37## A. 2,5-Dichlorophenylthioacetic acid

A mixture of 2,5-dichlorothiophenol (10.3 g, 57.5 mmol) and bromoaceticacid (8.03 g, 57.8 mmol) in water (225 mL) was treated with 10N NaOH (13mL, 130 mmol) and the mixture was heated at 100° C. for 1 h. Thereaction mixture was then cooled to 0° C. and acidified to pH 1 with 6NHCl. The product precipitated and was collected by filtration to give13.0 g (95% yield) of 2,5-dichlorophenylthioacetic acid as whitecrystals, m.p. 118° C. ¹ H NMR (300 MHz, CDCl₃) δ3.74 (s, 2H), 7.15 (dd,J=2, 9 Hz, 1H), 7.32 (d, J=9 Hz, 1H), 7.36 (d, J=2 Hz, 1H). Anal. Calcd.for C₈ H₆ O₂ SCl₂ : C, 40.53; H, 2.55. Found: C, 40.46; H, 2.64.

B.(6R)-trans-3-Chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester

Method a: A solution of 2,5-dichlorophenylthioacetic acid (13.0 g, 54.9mmol) in methylene chloride (55 mL) and thionyl chloride (10 mL, 137mmol) was heated at reflux for 3 h. The reaction mixture was allowed tocool to room temperature and was concentrated in vacuo. The residue wasevaporated two times from toluene to give 14 g of2,5-dichlorophenylthioacetyl chloride (100% yield) as a slightly coloredproduct which was used in the next step without purification. ¹ H NMR(300 MHz, CDCl₃) δ4.13 (s, 2H), 7.22 (dd, J=2, 9 Hz, 1H), 7.35 (d, J=9Hz, 1H), 7.39 (d, J=2 Hz, 1H).

(6R)-trans-3-Chloromethyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester, HCl salt was stirred in a biphasic mixture ofEtOAc and saturated NaHCO₃ for 0.5 h. The layers were separated, and theorganic solution was dried over anhydrous MgSO₄, filtered, andconcentrated to dryness. The free base (9.15 g, 22.0 mmol) was dissolvedin THF (200 mL), cooled to 0° C., and treated with N-methylmorpholine(3.34 g, 33.0 mmol) and 2,5-dichlorophenylthioacetyl chloride (6.75 g,26.4 mmol). The reaction mixture was stirred for 1 h at 0° C., dilutedwith EtOAc (1000 mL) and washed with water (1000 mL) and brine (100 mL).The organic solution was then dried (MgSO₄) and the solvents wereevaporated in vacuo. The residue was stirred with ether (100 mL). Theproduct solidified and was collected by filtration to give 12.0 g (86%yield) of(6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)-thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester, m.p. 120° C. ¹ H NMR (300 MHz, CDCl₃) δ3.43 (d,J=18 Hz, 1H), 3.59 (d, J=18 Hz, 1H), 3.69 (d, J=17 Hz, 1H), 3.79 (d,J=17 Hz, 1H), 4.36 (d, J=12 Hz, 1H) 4.41 (d, J=12 Hz, 1H), 4.98 (d, J=5Hz, 1H), 5.81 (dd, J=5, 9 Hz, 1H), 6.98 (s, 1H), 7.14-7.44 (m, 14H).Anal. Calcd for C₂₉ H₂₃ N₂ O₄ S₂ Cl₃ : C, 54.94; H, 3.66; N, 4.42.Found: C, 55.18; H, 3.84; N, 4.62.

Method b:(6R)-trans-3-Chloromethyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester, HCl salt (Otsuka, 248 g, 0.55 mol) was treatedwith NaHCO₃ (56 g, 0.66 mol) in water (1.6 L) at 0° C. The mixture wasstirred at 0° C. for 0.5 h and then CH₂ Cl₂ (1.5 L) was added. Thebiphasic mixture was filtered through Celite and the Celite pad waswashed with CH₂ Cl₂ (2 L total). The layers were separated and theorganic solution was dried over anhydrous MgSO₄, filtered, andconcentrated to a volume of ca. 2 L. The free amine solution was thenadded to a mixture of 2,5-dichlorothiophenylacetic acid (130 g, 0.55mol) and dicyclohexylcarbodiimide (144 g, 0.70 mol) in THF (1 L) at roomtemperature. The reaction mixture was stirred for 2.5 h and then wasfiltered through Celite, washing the Celite pad with several portions ofacetone. The filtrate was concentrated in vacuo to give a solid mass.The solid was slurried in Et₂ O and then collected by filtration,washing the solid with several portions of Et₂ O. The solid was driedunder high vacuum over P₂ O₅ to give 268 g (77% yield) of(6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester (see above for analytical data).

C.(6R)-trans-3-(4-Pyridylthiomethyl)-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester

A solution of(6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester (6.00 g, 9.46 mmol) in acetone (100 mL) was treatedwith sodium iodide (4.26 g, 28.4 mmol). The mixture was stirred at 20°C. for 3 h and then condensed under reduced pressure to a volume of 50mL. The concentrated solution was diluted with EtOAc (200 mL) and washedwith ice water (100 mL). The organic solution was washed with saturatedNaHSO₄ (20 mL), dried (MgSO₄), and evaporated under reduced pressure.The residue was stirred with ether (30 mL). The product solidified andwas collected by filtration to give 6.40 g of(6R)-trans-3-iodomethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester (93% yield) as a buff solid, m.p. 124° C. ¹ H NMR(300 MHz, CDCl₃) δ3.43 (d, J=18 Hz, 1H), 3.69 (d, J=17 Hz, 1H), 3.70 (d,J=18 Hz, 1H), 3.78 (d, J=17 Hz, 1H), 4.27 (d, J=9 Hz, 1H), 4.33 (d, J=9Hz, 1H), 4.96 (d, J=5 Hz, 1H), 5.75 (dd, J=5, 9 Hz, 1H), 7.00 (s, 1H),7.20-7.46 (m, 14H). Anal. Calcd. for C₂₉ H₂₃ N₂ O₄ S₂ Cl₂ I: C, 48.01;H, 3.20; N, 3.86. Found: C, 48.00; H, 3.14; N, 3.76.

(6R)-trans-3-Iodomethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester (3.00 g, 4.14 mmol) was dissolved in THF (50 mL) at0° C. and treated with 4-mercaptopyridine (0.504 g, 4.54 mmol). Asolution of 2,6-lutidine (0.576 g, 5.38 mmol) in THF (1 mL) was addednext, and the reaction mixture was stirred at 0° C. for 0.5 h and thenat 20° C. for 1 h. The mixture was diluted with ethyl acetate (500 mL)and the organic solution was washed with water (2×500 mL) and brine (100mL). The solution was then dried (MgSO₄) and evaporated under reducedpressure to give an oil which was treated with Et₂ O (50 mL) to give asolid. The solid was collected by filtration and purified by columnchromatography on silica gel (CH₂ Cl₂ to 30% EtOAc/CH₂ Cl₂) to give 1.50g of(6R)-trans-3-[(4-pyridylthiomethyl]-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester as a tan solid (49% yield), m.p. 122° C. ¹ H NMR(300 MHz, CDCl₃) δ3.37 (d, J=18 Hz, 1H), 3.52 (d, J=18 Hz, 1H), 3.68 (d,J=17 Hz, 1H), 3.76 (d, J=17 Hz, 1H), 3.96 (d, J=13 Hz, 1H), 4.16 (d,J=13 Hz, 1H), 4.93 (d, J=5 Hz, 1H), 5.76 (dd, J=5, 9 Hz, 1H), 6.95-7.42(m, 16H), 7.49 (d, J=9 Hz, 1H), 8.29 (d, J=6 Hz, 2H). Anal. Calcd. forC₃₄ H₂₇ N₃ O₄ S₃ Cl₂ : C, 57.62; H, 3.84; N, 5.93. Found: C, 57.27; H,3.68; N, 5.79.

D.1-[N-(p-Methoxybenzylcarboxymethyl)-N-(3-t-butyloxycarbonylamino-1-propyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumbromide

1. Preparation ofN-(p-methoxybenzylcarboxymethyl)-N-[(3-t-butyloxycarbonylamino)-1-propyl]bromoacetamide

To a -78° C. solution of p-methoxybenzyl alcohol (6.91 g, 50 mmol) andtriethylamine (6.95 mL, 50 mmol) in anhydrous CH₂ Cl₂ (50 mL) was addeda solution of bromoacetyl bromide (10.1 g, 50 mmol) in CH₂ Cl₂ at -78°C. under nitrogen, over a period of 10 min. The cooling bath wasremoved, and the reaction mixture was stirred for 2 h. The mixture waswashed with water and saturated sodium chloride solution, dried overanhydrous sodium sulfate, filtered, and concentrated to provide 12 g(93% yield) of p-methoxybenzyl bromoacetate as a dark colored oil whichwas used in the next reaction without purification. A portion waspurified by column chromatography on silica gel (elution with 20% ethylacetate/hexanes) to give a clear, colorless oil. ¹ H NMR (300 MHz,CDCl₃) δ3.79 (s, 3H), 3.83 (s, 2H), 5.12 (s, 2H), 6.87 (m, 2H), and 7.30(m, 2H); IR (film) 1738 cm⁻¹ ; MS (ESI/NH₄ OAc) M+NH₄ ⁺ =276.

To a cold (0°-5° C.) solution of3-(t-butyloxycarbonylamino)-1-propylamine (4.00 g, 23 mmol) andtriethylamine (2.8 mL, 20 mmol) in anhydrous CH₂ Cl₂ (15 mL) was addedslowly a solution of p-methoxybenzyl bromoacetate (5.18 g, 20 mmol) inanhydrous CH₂ Cl₂ (10 mL) over a period of 2.5 h. The mixture wasstirred at 0°-5° C. for 2 h, at which time TLC indicated that thereaction was complete. The mixture was washed with water and saturatedsodium chloride solution, dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give a dark residue. The crude material waspurified by column chromatography on silica gel (elution with 50% ethylacetate/hexane) to afford 2.81 g (40% yield) of p-methoxybenzyl[3-(t-butyloxycarbonylamino)-1-propylamino]acetate as an amber oil. ¹ HNMR (300 MHz, CDCl₃) δ1.41 (s, 9H), 1.61 (quint, J=7 Hz, 2H), 2.63 (t,J=7 Hz, 2H), 3.17 (q, J=6 Hz, 2H), 3.38 (s, 2H), 3.78 (s, 3H), 5.07 (s,2H), 6.86 (m, 2H), and 7.26 (m, 2H); IR (film), 1736, 1708 cm⁻¹ ; MS(isobutane-DCI) MH⁺ =353. Anal. Calcd. for C₁₈ H₂₈ N₂ O₅ : C, 61.35; H,8.01; N, 7.95. Found: C, 60.87; H, 8.30; N, 7.89.

To a cold (0°-5° C.) solution of[3-(t-butyloxycarbonylamino)-1-propylamino]acetate (1.41 g, 4.0 mmol)and triethylamine (0.56 mL, 4.0 mmol) in anhydrous CH₂ Cl₂ (10 mL) wasadded over 5 min a solution of bromoacetyl bromide (0.81 g, 4.0 mmol) inCH₂ Cl₂ under nitrogen. The reaction mixture was stirred at 0°-5° C. for50 min and then diluted with CH₂ Cl₂, washed with water and saturatedsodium chloride solution, dried over anhydrous sodium sulfate, filtered,and concentrated to give 1.81 g of an oily solid. Trituration withdiethyl ether gave 1.35 g (71% yield) ofN-(p-methoxybenzylcarboxymethyl)-N-[3-(t-butyloxy-carbonylamino)-1-propyl]bromoacetamideas white crystals, mp 79°-81° C. ¹ H NMR (300 MHz, CDCl₃) δ Two amideresonance structures: 1.40 and 1.42 (2 s, 9H), 1.60 and 1.80 (2 quints,2H), 3.05 and 3.12 (2 m, 2H), 3.43 (m, 2H), 3.73 and 3.89 (2 s, 2H),3.79 and 3.80 (2 s, 3H), 4.05 and 4.11 (2 s, 2H), 4.60 and 5.28 (2 br s,1H), 5.08 and 5.12 (2 s, 2H), 6.88 (m, 2H), and 7.27 (m, 2H); IR (KBr)1736, 1684, and 1662 cm⁻¹ ; MS (ESI) MH⁺ =473. Anal. Calcd. for C₂₀ H₂₉BrN₂ O₆ : C, 50.75; H, 6.17; N, 5.92. Found: C, 50.78; H, 6.22; N, 5.78.

2. Preparation of1-[N-(p-Methoxybenzylcarboxymethyl)-N-(3-t-butyloxycarbonylamino-1-propyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumbromide

A solution of(6R)-trans-3-[(4-pyridylthiomethyl]-7-[(2,5-dichlorophenyl)-thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,diphenylmethyl ester (0.43 g, 0.60 mmol) in DMF (5 mL) was treated withN-(p-methoxybenzylcarboxymethyl)-N-[(3-t-butyloxycarbonylamino)-1-propyl]bromoacetamide(0.57 g, 1.2 mmol) at room temperature under nitrogen. After 96 h, thereaction mixture was added slowly to stirred diethyl ether (50 mL). Agum separated. The solvent was decanted and the gum was triturated withfresh diethyl ether to give a solid. The solid was collected byfiltration, washed with additional ether, and dried to give 0.71 g(quantitative yield) of1-[N-(p-methoxybenzylcarboxymethyl)-N-(3-t-butyloxycarbonylamino-1-propyl)-carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridinium bromide. ¹ H NMR (DMSO-d₆, 300 MHz)δ1.39 (s, 9H), 1.45 -1.84 (m, 2H), 2.81-3.07 (m, 2H), 3.24-3.45 (m, 2H),3.55 (d, J=18 Hz, 1H), 3.74 (s, 2H), 3.82 (d, J=18 Hz, 1H), 3.92 (s,2H), 4.13 (s, 1H), 4.45 (s, 1H), 5.05 (s, 2H), 5.18 (d, J=5 Hz, 1H),5.45 (s, 1H), 5.53 (dd, J=5,8 Hz, 1H), 5.55 (s, 1H), 6.84 -6.95 (m, 4H),7.14-7.53 (m, 12H), 7.92 (m, 2H), 8.56 (m, 2H), and 9.33 (d, J=8 Hz,1H); MS (ESI): M⁺ =1100.

E.1-[N-(Carboxymethyl)-N-(3-amino-1-propyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo-[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumbromide, trifluoroacetate salt

A mixture of1-[N-(p-methoxybenzylcarboxymethyl)-N-(3-t-butyloxycarbonylamino-1-propyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumbromide (0.70 g, 0.59 mmol) in CH₂ Cl₂ (6 mL) and anisole (0.6 mL) wastreated with trifluoroacetic acid (6 mL) at room temperature. Theresulting solution was stirred for 1 h and then concentrated in vacuo.Diethyl ether (30 mL) was added to give a nearly colorless precipitate.The solid was collected by filtration and dried to provide 0.47 g (87%yield) of1-[N-(carboxymethyl)-N-(3-amino-1-propyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumbromide, trifluoroacetate salt as a light yellow solid. ¹ H NMR(DMSO-d₆, 300 MHz) δ1.63-2.05 (m, 2H), 2.55-3.05 (m, 2H), 3.26-3.66 (m,2H), 3.69 (d, J=18 Hz, 1H), 3.80 (d, J=18 Hz, 1H), 3.89 (s, 2H),4.00-4.38 (m, 2H), 4.26-4.50 (m, 1H), 5.12 (d, J=5 Hz, 1H), 5.42 (s,1H), 5.60 (s, 1H), 5.67 (dd, J=5,8 Hz, 1H), 7.22 (dd, J=2,8 Hz, 1H),7.39-7.58 (m, 2H), 8.00 (m, 2H), 8.55 (m, 2H), and 9.29 (d, J=8 Hz, 1H);IR (KBr) 1776 cm⁻¹ ; MS (ESI) M⁺ =714. Anal. Calcd. for C₂₈ H₂₉ Cl₂ N₅O₇ S₃.HBr. CF₃ CO₂ H: C, 39.61; H, 3.44; N, 7.70. Found: C, 39.72; H,3.60; N, 7.48.

EXAMPLE 2

1-[(1S)-1-(3-Amino-1-propyl)-N-(carboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt ##STR38## A.(6R)-trans-3-Chloromethyl-7-[(2,5-dichlorophenyl)-thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A slurry of(6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylatediphenylmethyl ester (10.0 g, 15.8 mmol) in CH₂ Cl₂ (200 mL) at 0° C.was treated with anisole (24 mL) and then trifluoroacetic acid (80 mL).The resulting solution was stirred for 1 h at 0° C. and thenconcentrated under reduced pressure. The residue was stirred with Et₂ O,and the resulting solid was collected by filtration to give 5.20 g of(6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)-thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid as a white solid (70% yield), m.p. 125° C. ¹ H NMR (300 MHz,DMSO-d₆) δ3.51 (d, J=18 Hz, 1H), 3.70 (d, J=18 Hz, 1H), 3.91 (s, 2H),4.52 (d, J=11 Hz, 1H), 4.58 (d, J=11 Hz, 1H), 5.13 (d, J=5 Hz, 1H), 5.70(dd, J=5, 8 Hz, 1H), 7.24 (dd, J=2, 8 Hz, 1H), 7.47 (dd, J=2, 8 Hz, 2H),9.28 (d, J=8 Hz, 1H).

B.1-[(1S)-1-(3-t-Butyloxycarbonylamino-1-propyl)-N-(t-butylcarboxymethyl)-carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)-acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumchloride

1. Preparation of1-[N-(t-butylcarboxymethyl)-1-[(t-butyloxycarbonylamino)propyl]-1-carbamoylmethyl]-4-thiopyridone

A solution of(2S)-[2-(benzyloxycarbonylamino)-5-(t-butyloxycarbonylamino)]pentanoicacid (2.50 g, 6.82 mmol) in CH₂ Cl₂ (100 mL) was treated withN-hydroxysuccinimide (0.785 g, 6.82 mmol) followed bydicyclohexylcarbodiimide (1.41 g, 6.82 mmol). The mixture was stirredfor 3 h and then treated with glycine t-butyl ester (0.895 g, 6.82 mmol,liberated from its HCl salt by dissolving in 1:1 dioxane/water andtreating with 1 equiv. of sodium bicarbonate). After 18 h, the solventswere removed in vacuo, and the crude product was purified by flashchromatography on silica gel (elution with 5-10% MeOH/CH₂ Cl₂) to give1.89 g (58% yield) of(2S)-N-t-butylcarboxymethyl-2-(benzyloxycarbonylamino)-5-(t-butyloxycarbonylamino)pentanamideas a colorless oil. ¹ H NMR (300 MHz, CDCl₃) δ1.42 (s, 9H), 1.44 (s,9H), 1.56 (m, 2 n), 1.90 (m, 2H), 3.09 (m, 1H), 3.36 (br s, 1H), 3.84(dd, J=6, 21 Hz, 1H), 3.98 (dd, J=6, 21 Hz, 1H), 4.40 (br s, 1H), 4.70(br s, 1H), 5.11 (s, 2H), 5.52 (d, J=6 Hz, 1H), 6.88 (br s, 1H) and 7.37(m, 5H).

A solution of(2S)-N-t-butylcarboxymethyl-2-(benzyloxycarbonylamino)-5-(t-butyloxycarbonylamino)pentanamide(1.09 g, 2.27 mmol) in ethanol (30 mL) was treated with acetic acid(0.13 mL, 2.27 mmol). This solution was placed under a nitrogenatmosphere in a Parr bottle and then treated with 10% palladium oncarbon (0.10 g, 0.09 mmol) and the resulting mixture was shaken in aParr apparatus under 50 psi of hydrogen for 18 h. Filtration throughCelite with the aid of 30 mL of water, followed by concentration of thefiltrate in vacuo gave 0.903 g (98% yield) of the acetic acid salt of(2S)-N-t-butylcarboxymethyl-2-amino-5-(t-butyloxycarbonylamino)pentanamideas a colorless oil. ¹ H NMR (300 MHz, DMSO-d₆) δ1.35 (s, 9H), 1.39 (s,9H), 1.39-1.71 (m, 4H), 1.84 (s, 3 H, CH₃ CO₂ ⁻), 2.88 (q, J=6 Hz, 2H),3.16-3.20 (m, 1H), 3.71 (d, J=4 Hz, 1H), 3.72 (d, J=4 Hz, 1H), 3.98 (brs, 3 H, NH₃ ⁺), 6.76 (t, J=5 Hz, 1H), and 8.22 (t, J=6 Hz, 1H); 13C NMR(75 MHz, DMSO-d₆) δ21.76, 25.83, 27.70, 28.27, 32.07, 33.35, 41.19,54.05, 77.32, 80.57, 155.58, 168.96, 172.54, and 175.05; IR (film) 3320,1739, 1690, 1534, 1368, 1162 cm⁻¹ ; MS (DCI) m/e 346 (MH⁺). Anal. Calcd.for C₁₆ H₃₁ N₃ O₅.C₂ H₄ O₂.0.25 H₂ O: C, 52.73; H, 8.73; N, 10.25.Found: C, 52.57; H, 8.94; N, 10.38.

A solution of the acetic acid salt of(2S)-N-t-butylcarboxymethyl-2-amino-5-(t-butyloxycarbonylamino)pentanamide(0.813 g, 2.00 mmol) in ethanol (10 mL) was treated with 1N NaOH (2.00mL, 2.00 mmol). To this solution was added 4-thiopyrone (0.225 g, 2.00mmol) (ref.: European Patent Application No. 209751). After stirring for19 h, the reaction mixture was concentrated in vacuo to give 1.00 g ofthe crude product as a red oil. Purification by flash chromatography onsilica gel (elution with 7.5% MeOH/CH₂ Cl₂) gave 0.498 g (57% yield) of1-[(1S)-N-(t-butylcarboxymethyl)-1-[(t-butyloxycarbonylamino)propyl]]-carbamoylmethyl-4-thiopyridoneas a red solid. ¹ H NMR (300 MHz, DMSO-d₆) δ1.35 (s, 9H), 1.37 (s, 9H),1.58-1.72 (m, 2H), 1.90-2.03 (m, 2H), 2.88-2.96 (m, 2H), 3.69-3.85 (m,2H), 4.75 (m, 1H), 6.86 (t, J=6 Hz, 1H), 7.15 (d, J=7 Hz, 2H), 7.59 (d,J=7 Hz, 2H), and 8.76 (t, J=6 Hz, 1H); ¹³ C NMR (75 MHz, DMSO-d₆)δ24.47, 25.61, 27.67, 28.24, 28.53, 33.36, 41.59, 67.00, 77.55, 80.96,129.91,135.12, 155.61, 168.05, 168.29, and 190.46; IR (KBr) 3328, 1742,1688, 1622, 1530, 1160, 1112 cm⁻¹ ; MS (ESI) m/e 440 (MH⁺). Anal. Calcdfor C₂₁ H₃₃ N₃ O₅ S: C, 57.38; H, 7.57; N, 9.56. Found: C, 57.46; H,7.82; N, 9.34.

2. Preparation of1-[(1S)-1-(3-t-butyloxycarbonylamino-1-propyl)-N-(t-butylcarboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumchloride

A solution of1-[(1S)-N-(t-butylcarboxymethyl)-1-[(t-butyloxycarbonylamino)propyl]]carbamoylmethyl-4-thiopyridone(0.457 g, 1.04 mmol) in DMF (5 mL) was added to a solution of(6R)-trans-3-chloromethyl-7-[(2,5-dichlorophenyl)thioacetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (0.489 g, 1.04 mmol) in DMF (5 mL). After 4 h, the reacton mixturewas concentrated in vacuo to give 0.950 g of a red oil. Trituration withdiethyl ether provided a solid which was collected by filtration to give0.850 g of nearly pure material. The solid was stirred with ether for 2h, and then collected by filtration and dried in vacuo to give 0.725 g(77% yield) of1-[(1S)-1-(3-t-butyloxycarbonylamino-1-propyl)-N-(t-butylcarboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumchloride as a tan solid. ¹ H NMR (300 MHz, DMSO-d₆) δ1.20 (m, 1H), 1.34(s, 9H), 1.36 (s, 9H), 1.54-1.67 (m, 1H), 2.14 (m, 1H), 2.25 (m, 1H),2.93 (m, 1H), 3.52 (d, J=18 Hz, 1H), 3.70-3.80 (m, 2H), 3.92 (s, 2H),4.30-4.47 (m, 2H), 5.14 (d, J=5 Hz, 1H), 5.57 (t, J=7 Hz, 1H), 5.67 (dd,J=5, 8 Hz, 1H), 6.88 (m, 1H), 7.23 (dd, J=2, 9 Hz, 1H), 7.44-7.48 (m,2H), 8.05 (d, J=7 Hz, 2H), 8.83 (d, J=7 Hz, 2H), and 9.30-9.32 (m, 2H);¹³ C NMR (75 MHz, DMSO-d₆) δ25.44, 27.20, 27.68, 28.24, 28.96, 33.67,34.12, 41.69, 47.49, 57.52, 59.38, 69.67, 77.59, 81.05, 122.53, 123.65,126.22, 126.28, 126.94, 128.86, 130.69, 132.52, 137.89, 142.21, 155.59,162.86, 163.32, 164.22, 167.05, 168.04, and 168.22; IR (KBr) 3328, 2978,1782, 1686, 1626, 1542, 1450, 1368, 1160 cm⁻¹ ; MS (ESI) m/e 870 (MH⁺).Anal. Calcd for C₃₇ H₄₅ N₅ O₉ S₃ Cl₂.HCl; C, 48.98; H, 5.11; N, 7.72.Found: C, 48.51; H, 5.11; N, 7.56.

C.1-[(1S)-1-(3-Amino-1-propyl)-N-(carboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumchloride trifluoroacetate salt

A slurry of1-[(1S)-1-(3-t-butyloxycarbonylamino-1-propyl)-N-(t-butylcarboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniumchloride (0.680 g, 0.750 mmol) in methylene chloride (20 mL) at 0° C.was treated with anisole (2.5 mL) followed by addition oftrifluoroacetic acid (9.2 mL). The resulting solution was stirred at 0°C. for 30 min and then at room temperature for 5 h. The reaction mixturewas concentrated in vacuo to give an oil. Trituration with ether gave asolid which was collected by filtration. The solid was slurried withacetone, collected by filtration, and dried in vacuo to give 0.219 g(33% yield) of1-[(1S)-1-(3-amino-1-propyl)-N-(carboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3yl]methylthio]pyridiniumchloride trifluoroacetate salt as a brown solid. ¹ H NMR (300 MHz,DMSO-d₆) δ1.32-1.57 (m, 2H), 2.27 (br s, 2H), 2.80 (br s, 2H), 3.20-3.47(m, 1H), 3.62 (d, J=18 Hz, 1H), 3.82 (br s, 2H), 3.92 (s, 2H), 4.38-4.57(m, 2H), 5.00-5.05 (m, 1H), 5.46 (br s, 1H), 5.57-5.62 (m, 1H), 7.24 (d,J=8 Hz, 1H), 7.45-7.48 (m, 2H), 7.60-7.80 (br s, 3H), 8.21-8.23 (m, 2H),8.70-8.82 (m, 2H), 9.15 (br s, 1H), and 9.26 (d, J=8 Hz, 1H); IR (KBr)3428, 1772, 1676, 1626, 1202 cm⁻¹ ; MS (ESI) m/e 714 (MH⁺). Anal. Calcdfor C₂₈ H₂₉ N₅ O₇ S₃ Cl₂.HCl.CF₃ CO₂ H.0.4 C₄ H₁₀ O: C, 42.42; H, 3.94;N, 7.83. Found: C, 42.16; H, 4.16; N, 7.69.

2D. Preparation of Additional Representative Thiopyridone Intermediates

The following additional thiopyridone intermediates were preparedaccording to the general method of Example 2(B) described above:

    __________________________________________________________________________    Intermediate                   .sup.1 H NMR Data      Ms                      __________________________________________________________________________                                                          Data                     ##STR39##                     1.16-1.21(m), 1.33(s), 1.48-1.56(m),                                          1.62-1.65(m), 3.57(q, J=6), 3.91(t, J=7),                                     6.0(d, J=7), 7.12(d, J=7), 7.60(d,                                                                   M.sup.+  = 340           ##STR40##                     1.34(s), 1.49-1.71(m), 2.34(s),                                               3.55-3.57(m), 3.86(t, J=8), 5.98(d, J=7),                                     7.02(s)                MH.sup.+  = 369          ##STR41##                     1.18(s), 1.40-1.65(m), 1.78-1.84(m),                                          3.94(brs), 7.15 (d, J=7), 7.59(d,                                                                    NA7)                     ##STR42##                     1.34(s), 1.40-1.75(m), 3.54-3.60(m),                                          3.94(t, J=6), 6.04 (d, J=6), 7.12(d, J=7),                                    7.60(d, J=7)           MH.sup.+  = 327          ##STR43##                     1.35(s), 1.46-1.71(m), 2.34(s),                                               3.53-3.63(m), 3.84-3.98(m), 3.98(m),                                          6.08(d, J=6), 7.02(s)  (M-H).sup.+  = 353       ##STR44##                     1.40-1.80(m), 2.30(s), 2.40(s),                                               3.05-3.15(m), 4.00-4.10(m), 7.19(d, J=8                                       Hz), 7.56(d, J=8 Hz)   NA                       ##STR45##                     1.16(t, J=7), 1.35(s), 1.51-1.73(m),                                          2.63(q, J=7), 3.51-3.60(m), 3.96(t, J=7),                                     6.03(d, J=6), 7.00(dd, J=2, 7), 7.08(d,                                       J=2), 7.59(d, J=7)     MH.sup.+  = 355          ##STR46##                     1.40(s), 1.75-1.95(m), 2.26(s),                                               3.05-3.30(m), 4.05-4.15(m), 4.95(brs),                                        7.05(s) 7.42(d, J=5), 7.70(d,                                                                        NA5)                     ##STR47##                     1.40(s), 1.50(s), 1.80-1.92(m), 2.50(m),                                      3.05-3.30(m) 3.60-3.70(m), 4.96(brs),                                         7.05(s), 7.15(d, J=5), 7.45(d,                                                                       NA5)                     ##STR48##                     1.34(s), 1.35-1.77(m), 3.48-3.58(m),                                          3.92(t, J=6), 5.95 (d, J=6), 7.12(d, J=7),                                    7.95(d, J=7)           MH.sup.+  = 327          ##STR49##                     1.34(s), 1.55-1.85(m), 2.33(s),                                               3.50-3.60(m), 3.85-3.95(m), 6.01(d, J=6),                                     7.01(s)                MH.sup.+  = 355          ##STR50##                     1.34(s), 1.83-2.12(m), 3.59-3.76(m),                                          3.98(t, J=7), 6.45(d, J=7), 7.12(d, J=7),                                     7.60(d, J=7)           M.sup.+  = 312           ##STR51##                     1.32(s), 3.39(dd, J=6, 10), 4.10(dd,                                          J=6,13), 4.29-4.34(m), 6.14(d, J=6),                                          7.07(d, J=7), 7.40(d, J=7)                                                                           M.sup.+  = 298           ##STR52##                     1.01-1.11(m), 1.34(s), 1.72-1.85(m),                                          2.00-2.12(m), 2.83(q, J=6), 4.29(dd, J=4,                                     11), 6.74(t, J=5), 7.08(d, J=7), 7.57(d,                                      J=7)                   (M-H).sup.+  339         ##STR53##                     1.01-1.16(m), 1.33(s), 1.68-1.82(m),                                          2.02-2.12(m), 2.80-2.93(m), 3.42(brs),                                        4.31(q, J=5), 6.81(t, J=5), 7.09(d, J=7),                                     7.57(d, J=7)           MH.sup.+  = 327          ##STR54##                     1.09-1.23(m), 1.36-1.50(m), 1.91-2.06(m),                                     3.02-3.12 (m), 4.71(dd, J=4, 11), 7.15(d,                                     J=7), 7.22(s), 7.62(d, J=7),                                                                         M.sup.+  = 268           ##STR55##                     1.33(s), 1.35(s), 2.26-2.43(m),                                               3.30-3.45(m), 3.82- 3.90(m), 4.00-4.07(m),                                    4.79-4.88(m), 7.12(d, J=7), 7.66-7.70(m)                                                             (M-H).sup.+  = 323       ##STR56##                     1.35(s), 1.37(s), 1.58-1.72(m),                                               1.90-2.03(m), 2.88- 2.96(m), 3.69-3.85(m),                                    4.75(m), 6.86(t, J=6), 7.15(d, J=7),                                          7.59(d, J=7), 8.76(t, J=6)                                                                           MH.sup.+  = 440          ##STR57##                     (D.sub.2 O)1.26-1.71(m), 3.06(t, J=6),                                        3.61-3.72(m), 4.83- 4.89(m), 7.42(d, J=7),                                    7.68(d, J=7)           NA                       ##STR58##                     (D.sub.2 O)1.55-1.95(m), 3.12-3.35(m),                                        4.12-4.30(m), 5.05 (s), 7.55(d, J=8),                                         7.75(d, J=8)           MH.sup.+  = 326          ##STR59##                     1.08-1.80(m, overlaps with 2 singlets),                                       1.34(s), 1.40 (s), 3.55-3.81(m),                                              3.84-4.05(m), 6.81(d, J=12), 7.11(d, J=8),                                    7.63(d, J=8), 8.05-8.20(m)                                                                           MH.sup.+  = 454          ##STR60##                     1.24-1.71(m, overlaps with 2 singlets),                                       1.32(s), 1.39 (s), 3.53-3.84(m),                                              3.88-4.05(m), 6.95(d, J=12), 7.13(d, J=8),                                    7.60(d, J=8), 8.10-8.34(m)                                                                           MH.sup.+  = 440          ##STR61##                     1.37(s), 1.45(s), 1.50-1.75(m), 3.87(m),                                      3.96(m), 7.12(d, J=7), 7.62(d, J=7),                                          9.08(d, J=6), 11.5(s)  MH.sup.+  = 469          ##STR62##                     1.33(s), 1.34(s), 1.94-1.98(m),                                               2.72-2.82(m), 3.39- 3.43(m), 3.96(brs),                                       4.78(brs), 7.11(d, J=7),                                                                             MH.sup.+  =             __________________________________________________________________________                                                          325                      NA = not available                                                       

The following compounds were prepared according to the generalprocedures of Examples 1 and 2 by varying the thiol starting materialand the pyridine or thiopyridone derivative:

    __________________________________________________________________________     ##STR63##                                                                    Example                                                                       No.  Ar            R.sup.1                  R.sup.2                                                                              R.sup.3                                                                         Isolated                 __________________________________________________________________________                                                         as                       3    2,5-dichlorophenyl                                                                           ##STR64##               H      H CF.sub.3 CO.sub.2 H,                                                          HCl salt                 4    2,5-dichlorophenyl                                                                           ##STR65##               2,6-dimethyl                                                                           CF.sub.3 CO.sub.2 H,                                                          HCl salt                 5    2,5-dichlorophenyl                                                                           ##STR66##               H      H CF.sub.3 CO.sub.2 H,                                                          HCl salt                 6    2,5-dichlorophenyl                                                                           ##STR67##               H      H CF.sub.3 CO.sub.2 H                                                           salt                     7    2,6-dichloropyridin-4-yl                                                                     ##STR68##               H      H CF.sub.3 CO.sub.2 H,                                                          HCl salt                 8    3-bromophenyl                                                                                ##STR69##               H      H CF.sub.3 CO.sub.2 H,                                                          HCl salt                 9    3,5-dichloro-4-hydroxyphenyl                                                                 ##STR70##               H      H CF.sub.3 CO.sub.2 H                                                           salt                     10   2-chloro-5- trifluoromethylphenyl                                                            ##STR71##               H      H CF.sub.3 CO.sub.2 H,                                                          HCl salt                 11   3,5-dichloro-4-aminophenyl                                                                   ##STR72##               H      H CF.sub.3 CO.sub.2 H                                                           salt                     12   2,5-dimethylphenyl                                                                           ##STR73##               H      H CF.sub.3 CO.sub.2 H,                                                          HCl salt                 13   2,4,5-trichlorophenyl                                                                        ##STR74##               H      H CF.sub.3 CO.sub.2 H,                                                          HCl salt                 14   2,5-dichlorophenyl                                                                           ##STR75##               2,6-dimethyl                                                                           CF.sub.3 CO.sub.2 H                                                           salt                     15   2,6-dichloropyridin-4-yl                                                                     ##STR76##               2,6-dimethyl                                                                           CF.sub.3 CO.sub.2 H                                                           salt                     16   2,5-dichloro-4- hydroxymethylphenyl                                                          ##STR77##               2,6-dimethyl                                                                           HCl salt                 17   3-fluorophenyl                                                                               ##STR78##               2,6-dimethyl                                                                           HCl salt                 18   3-bromophenyl                                                                                ##STR79##               2,6-dimethyl                                                                           CF.sub.3 CO.sub.2 H,                                                          Cl salt                  19   2-chloro-5- trifluoromethylphenyl                                                            ##STR80##               2,6-dimethyl                                                                           CF.sub.3 CO.sub.2 H,                                                          HCl salt                 20   2,4,5-trichlorophenyl                                                                        ##STR81##               2,6-dimethyl                                                                           CF.sub.3 CO.sub.2 H,                                                          HCl salt                 21   2,5-dichlorophenyl                                                                           ##STR82##               2,3-dimethyl                                                                           HCl salt                 22   2,5-dichlorophenyl                                                                           ##STR83##               2-ethyl                                                                              H CF.sub.3 CO.sub.2 H,                                                          HCl salt                 23   2,5-dichlorophenyl                                                                           ##STR84##               2-methyl                                                                             H HCl salt                 24   2,5-dichlorophenyl                                                                           ##STR85##               2-(CH.sub.2).sub.3 NH.sub.2                                                          H HCl salt                 25   2,5-dichlorophenyl                                                                           ##STR86##               H      H CF.sub.3 CO.sub.2 H                                                           salt                     26   2,5-dichloro-4- hydroxymethylphenyl                                                          ##STR87##               H      H CF.sub.3 CO.sub.2 H                                                           salt                     27   2,5-difluorophenyl                                                                           ##STR88##               2,6-dimethyl                                                                           CF.sub.3 CO.sub.2 H                                                           salt                     28   2,5-dichlorophenyl                                                                           ##STR89##               H      H CF.sub.3 CO.sub.2 H,                                                          HCl salt                 29   2,5-dichlorophenyl                                                                           ##STR90##               H      H CF.sub.3 CO.sub.2 H                                                           salt                     30   2,5-dichlorophenyl                                                                           ##STR91##               H      H CF.sub.3 CO.sub.2 H,                                                          HCl salt                 31   2,5-dichlorophenyl                                                                           ##STR92##               H      H CF.sub.3 CO.sub.2 H,                                                          HCl salt                 32   2,5-dichlorophenyl                                                                           ##STR93##               H      H HCl salt                 33   2,5-dichlorophenyl                                                                           ##STR94##               H      H CF.sub.3 CO.sub.2 H,                                                          HCl salt                 34   2,5-dichlorophenyl                                                                           ##STR95##               H      H HCl salt                 35   2,5-dichlorophenyl                                                                           ##STR96##               H      H HCl salt                 36   2,5-dichlorophenyl                                                                           ##STR97##               H      H CF.sub.3 CO.sub.2 H,                                                          HCl salt                 37   2,5-dichlorophenyl                                                                           ##STR98##               H      H CF.sub.3 CO.sub.2 H,                                                          HCl salt                 38   2,5-dichlorophenyl                                                                           ##STR99##               H      H CF.sub.3 CO.sub.2 H,                                                          HBr salt                 39   2,5-dichlorophenyl                                                                           ##STR100##              H      H CF.sub.3 CO.sub.2 H,                                                          HBr salt                 40   3-iodophenyl                                                                                 ##STR101##              H      H CF.sub.3 CO.sub.2 H                                                           salt                     41   3-chlorophenyl                                                                               ##STR102##              H      H CF.sub.3 CO.sub.2 H                                                           salt                     42   3-iodophenyl                                                                                 ##STR103##              H      H CF.sub.3 CO.sub.2 H                                                           salt                     43   2,5-dichlorophenyl                                                                           ##STR104##              H      H CF.sub.3 CO.sub.2 H                                                           salt                     44   2,5-dichlorophenyl                                                                           ##STR105##              H      H HCl salt                 45   2,5-dichlorophenyl                                                                           ##STR106##              H      H CF.sub.3 CO.sub.2 H,                                                          Cl                       __________________________________________________________________________                                                         salt                 

                  TABLE                                                           ______________________________________                                        MS DATA                                                                       Compound of               Method for                                          Example No.   MS          IV to I                                             ______________________________________                                        1             M.sup.+  = 714                                                                            1                                                   2             MH.sup.+  = 714                                                                           2                                                   3             M.sup.+  = 671                                                                            2                                                   4             MH.sup.+  = 699                                                                           2                                                   5             M.sup.+  = 671                                                                            2                                                   6             MH.sup.+  = 657                                                                           2                                                   7             MH.sup.+  = 658                                                                           2                                                   8             MH.sup.+  = 667                                                                           2                                                   9             M.sup.+  = 673                                                                            2                                                   10            MH.sup.+  = 691                                                                           2                                                   11            MH.sup.+  = 672                                                                           2                                                   12            MH.sup.+  = 617                                                                           2                                                   13            MH.sup.+  = 691                                                                           2                                                   14            MH.sup.+  = 685                                                                           2                                                   15            MH.sup.+  = 686                                                                           2                                                   16            (M-H).sup.+ 2= 715                                              17            M.sup.+  = 635                                                                            2                                                   18            MH.sup.+  = 695                                                                           2                                                   19            MH.sup.+  = 719                                                                           2                                                   20            MH.sup.+  = 719                                                                           2                                                   21            MH.sup.+  = 685                                                                           2                                                   22            MH.sup.+  = 685                                                                           2                                                   23            M.sup.+  = 671                                                                            2                                                   24            M.sup.+  = 714                                                                            2                                                   25            M.sup.+  = 657                                                                            2                                                   26            MH.sup.+  = 687                                                                           2                                                   27            MH.sup.+  = 683                                                                           2                                                   28            M.sup.+  = 643                                                                            2                                                   29            MH.sup.+  = 629                                                                           2                                                   30            M.sup.+  = 671                                                                            2                                                   31            M.sup.+  = 657                                                                            2                                                   32            MH.sup.+  = 699                                                                           2                                                   33            M.sup.+  = 657                                                                            2                                                   34            M.sup.+  = 756                                                                            2                                                   35            M.sup.+  = 756                                                                            1                                                   36            M.sup.+  = 728                                                                            2                                                   37            M.sup.+  = 714                                                                            2                                                   38            M.sup.+  = 700                                                                            1                                                   39            M.sup.+  = 742                                                                            1                                                   40            MH.sup.+  = 715                                                                           2                                                   41            MH.sup.+  = 623                                                                           2                                                   42            MH.sup.+  = 715                                                                           2                                                   43            MH.sup.+  = 699                                                                           2                                                   44            MH.sup.+  = 757                                                                           2                                                   45            MH.sup.+  = 655                                                                           2                                                   ______________________________________                                    

    TABLE      - NMR DATA      ##STR107##                                                                              C     omp.      of Ex.      No. H-2 H-6 H-7 H-3' H-7' NH ArH SPyrH R      1 3.69(d, J=18) 5.12(d, J=5) 5.67(dd, J=5,8) 4.26-4.50(m, 3.89(s)     9.29(d, J=8) 7.22(dd, J=2,8) 8.00(m) 1.63-2.05(m)       3.80(d, J=18)   overlaps with R)   7.37-7.58(m) 8.55(m) 2.55-3.05(m)                 3.26-3.66(m)               4.00-4.38(m,               overlaps with H-3')               5.42(s)               5.60(s)      2 3.20-3.47(m) 5.00-5.05(m) 5.57-5.62(m) 4.38-4.57(m) 3.92(s) 9.26(d,     J=8) 7.24(d, J=8) 8.21-8.23(m) 1.32-1.57(m)       3.62(d, J=18)      7.45-7.48(m) 8.70-8.82(m) 2.27(br s)               2.80(br s)               3.82(br s)               5.46(br s)               7.60-7.80(m)               9.15(br s)      3 3.40(d, J=17) 4.99(d, J=5) 5.55(dd, J=5,8) 4.35-4.58(m) 3.92(s)     9.30(d, J=8) 7.22(dd, J=2,8) 8.06(d, J=6) 1.04-1.40(m)       3.59(d, J=17)   4.56(d, J=13)   7.43-7.48(m) 8.74(d, J=6) 1.77-1.85(m)               3.56(br s)               4.43(br s)      4 3.43(d, J=17) 5.04(d, J=5) 5.58-5.61(m) 4.49(d, J=13) 3.94(s) 9.29(d,     J=8) 7.25(d, J=8) 2.74(s, PyrMe) 1.53(br s)       3.60-3.66(m,   4.31-4.52(m,   7.46-7.49(m) 7.87(s) 1.79(br s)       overlaps with R)   overlaps with R)     3.60-3.77(m,               overlaps with H-2)               4.31-4.52(m, overlaps               with H-3')      5 3.47(d, J=17) 5.07(d, J=3) 5.57-5.62(m) 4.4-4.52(m, 3.94(s) 9.38(d,     J=8) 7.23(dd, J=2,8) 8.10(d, J=6) 1.36-1.39(m)       3.69(d, J=17)   overlaps with R)   7.44-7.47(m) 8.85(d, J=6) 1.79(br     s)               4.34-4.52(m,               overlaps with H-3')               8.38(br s)      6 3.47(d, J=17) 5.09(d, J=4) 5.64(dd, J=4,8) 4.35-4.51(m, 3.92(s)     9.29(d, J=8) 7.23(dd, J=2,8) 8.06(d, J=7) 1.75(br s)       3.69(d, J=17,   overlaps with R)   7.44-7.74(m) 8.77(d, J=7) 1.95(br     s)       overlaps with R)        3.63-3.75(m, overlaps               with H-2)               4.35-4.51(m, overlaps               with H-3')      7 3.42(d, J=17) 5.02(d, J=5) 5.57(dd, J=5,8) 4.37-4.58(m, 3.99(d,     9.42(d, J=8) 7.51(s) 8.10(d, J=6) 1.72(br s)       3.61(d, J=17)   overlaps with R) J=15)   8.73(d, J=6) 1.98(br s)                 4.07(d,    3.58-3.74(m)           J=15)    4.37-4.58(m,               overlaps with H-3')      8 3.43(d, J=18) 5.01(d, J=5) 5.56(dd, J=5,8) 4.30-4.57(m, 3.78(d,     9.22(d, J=8) 7.23(t, J=7) 8.09(br s) 1.73(br s)       3.62(d, J=18)   overlaps with R) J=15)  7.33(t, J=7) 8.57(br s)     2.02(br s)           3.85(d,   7.55(d, J=2)  3.55-3.75(m)           J=15)    4.30-4.57(m,               overlaps with H-3')      9 3.40(d, J=18) 4.96(d, J=5) 5.50(dd, J=5.8) 4.35-4.55(m, 4.68(s)     9.04(d, J=8) 7.39(s) 8.14(d, J=7) 1.65(br s)       3.61(d, J=18)   overlaps with R)    8.73(d, J=7) 1.90-2.00(m)               3.60-3.80(m)               4.35-4.55(m, overlaps               with H-3')      10 3.41(d, J=18) 5.00(d, J=5) 5.55(dd, J=5,8) 4.38(d, J=14) 3.99(s)     9.32(d, J=8) 7.53(d, J=8) 8.11(d, J=7) 1.69(br s)       3.59(d, J=18)   4.55(d, J=14)   7.68(d, J=8) 8.74(d, J=7) 2.07(br s)               7.80(s)  3.56(br s)               4.46(br s)      11 3.44(d, J=18) 5.02(d, J=4) 5.56(dd, J=4,8) 4.39(d, J=11) 3.59(s)     9.00(d, J=8) 7.36(s) 8.12(d, J=7) 1.60-1.80(m)       3.64(d, J=18)   4.45-4.55(m,    8.75(d, J=7) 1.90-2.10(m)          overlaps with R)     3.39-3.60(m)               4.45-4.55(m)      12 3.44(d, J=18) 5.03(d, J=5) 5.59(dd, J=5,8) 4.38(d, J=14) 3.73(s)     9.17(d, J=8) 6.87(d, J=8) 8.08(br s) 1.71(br s)       3.63(d, J=18)   4.48(d, J=14)   7.04(d, J=8) 8.74(br s) 1.99(br s)                 7.17(s)  3.60-3.73(m)               4.40-4.54(m)      13 3.41(d, J=17) 4.99(d, J=5) 5.54(dd, J=5,8) 4.36-4.59(m, 3.91(d,     9.32(d, J=8) 7.67(s) 8.11(d, J=6) 1.66(br s)       3.59(d, J=17)   overlaps with R) J=15)  7.84(s) 8.73(d, J=6) 2.00(br     s)           3.97(d,    3.56-3.70(m)           J=15)    4.36-4.59(m,               overlaps with H-3')      14 3.46(d, J=18) 5.10(d, J=5) 5.66(dd, J=5,8) 4.27-4.40(m, 3.90(s)     9.28(d, J=8) 7.23(dd, J=2,8) 2.72(s, PyrMe) 1.70-2.00(m)       3.70(d, J=18)   overlaps with R)   7.46(d, J=8) 7.84(s) 3.47-3.60(m)            4.45(d, J=12)   7.47(d, J=2)  4.27-4.40(m, overlaps               with H-3')      15 3.44(d, J=18) 5.07(d, J=5) 5.63(dd, J=5,8) 4.23-4.45(m, 3.99(s)     9.31(d, J=8) 7.49(s) 2.72(s, PyrMe) 1.74-2.03(m)       3.68(d, J=18)   overlaps with R)    7.80(s) 3.82(br s)          4.39(d, J=12)     4.23-4.45(m, over-               laps with H-3')      16 3.50(d, J=18) 5.18(d, J=5) 5.66(dd, J=5,8) 4.32(d, J=13) 3.89(s)     9.29(d, J=8) 4.47(s) 7.83(s) 1.83-2.10(m)       3.74(d, J=18)   4.39(d, J=13)   7.46(s) 2.78(br s, 3.84-3.99(m)                    7.51(s) PyrMe) 4.36(br s)               8.67(br s)      17 3.47(d, J=17) 5.11(d, J=4) 5.67(dd, J=4,8) 4.30-4.40(m) 3.76(d,     9.26(d, J=8) 6.95(app ddd, 7.84(br s) 1.83-2.03(m)           J=14)  J=2,9,10) 2.77(br s, 3.90-3.96(m)           3.80(d,  7.13(app d, J=10) PyrMe) 4.29-4.39(m)           J=14)  7.26(ddd, J=2,2,7)  8.69(br s)             7.32(app dd, J=9,14)      18 3.42(d, J=18) 5.03(d, J=5) 5.58(dd, J=5,8) 4.23-4.49(m, 3.79(s)     9.15(d, J=8) 7.22(t, J=8) 2.73(br s, 1.84(br s)       3.62(d, J=18)   overlaps with R)   7.33(t, J=8) PyrMe) 3.57-3.78(m)                7.55(s) 7.83(s) 4.23-4.49(m,               overlaps with H-3')      19 3.37(d, J=18) 4.99(d, J=5) 5.55(dd, J=5,8) 4.20-4.33(m, 3.98(s)     9.29(d, J-8) 7.53(d, J=8) 2.72(br s, 1.85(br s)       3.55(d, J=18)   overlaps with R)   7.68(d, J=8) PyrMe) 3.53(br s)               4.48(d, J=14)   7.80(s) 7.90(s) 4.20-4.33(m,               overlaps with H-3')      20 3.40(d, J=18) 5.04(d, J=5) 5.59(dd, J=5,8) 4.25-4.55(m, 3.97(s)     9.31(d, J=8) 7.69(s) 2.75(br s, 1.90(br s)       3.59(d, J=18)   overlaps with R)   7.84(s) PyrMe) 3.57-3.74(m)                      7.85(s) 4.25-4.55(m,               overlaps with H-3')      21 3.51(d, J=18) 5.16(d, J=5) 5.71(dd, J=5,8) 4.32-4.42(m, 3.93(s)     9.28(d, J=8) 7.23(dd, J=2,8) 2.35(s, PyrMe) 1.80-2.00(m)       3.76(d, J=18)   overlaps with R)   7.46(d, J=8) 2.72(s, PyrMe)     4.32-4.42(m,             7.50(d, J=2) 7.85(d, J=8) overlaps with H-3')              8.75(d, J=8) 4.50-4.60(m)      22 3.44(d, J=17) 5.05(d, J=5) 5.59(dd, J=5,8) 4.36-4.60(m, 3.96(s)     9.30(d, J=8) 7.25(dd, J=2,8) 1.22-1.38(m, 1.62-2.08(m)       3.68(d, J=17)   overlaps with R)   7.47(d, J=8) PyrEt) 3.50-3.68(m)                7.50(d, J=2) 2.95-3.15(m, 4.36-4.60(m, overlaps              PyrEt) with H-3')              7.96(br s)              8.00(br s)              8.71(br s)      23 3.48(d, J=18) 5.14(d, J=4) 5.67(dd, J=4,8) 4.40-4.50(m, 3.93(s)     9.28(d, J=8) 7.24(dd, J=2,8) 7.88(d, J=7) 1.80-2.10(m)       3.72(d, J=18)   overlaps with R)   7.46(d, J=8) 7.96(s) 3.82-4.00(m)               7.47(app s) 8.82(d, J=7) 4.40-4.50(m, overlaps              2.76(br s, with H-3')              PyrMe) 8.18(br s)               8.57(br s)               8.66(br s)      24 3,21(d, J=18) 5.16(d, J=4) 5.72(dd, J=4,8) 4.42-4.55(m) 3.90(s)     9.34(d, J=7) 7.24(dd, J=2,8) 1.60-2.10(m, 1.60-2.10(m,       3.39(d, J=18)      7.47(d, J=8) SPyrCH.sub.2 CH.sub.2, overlaps with               7.48(app s) overlaps with SPyrCH.sub.2      CH.sub.2)                        R) 2.70-2.81(m,              2.70-2.81(m, overlaps with              SPyrCH.sub.2, SPyrCH.sub.2)              overlaps with 3.00-3.24(m)              R) 3.90-4.02(m)              2.83-3.00(m) 8.16(br s)              7.91(d, J=7) 8.45(br s)              7.99(s) 8.56(br s)              8.85(d, J=7) 8.64(br s)      25 3.41(d, J=18) 5.01(d, J=5) 5.54(dd, J=5,8) 4.39(d, J=14) 3.93(s)     9.34(d, J=8) 7.22(dd, J=2,8) 8.10(d, J=7) 1.71(br s)       3.60(d, J=18)   4.55(d, J=14)   7.44-7.48(m) 8.76(d, J=7) 1.90-2.10(m)               3.57(br s)               4.43(br s)               4.35-4.55(m)      26 3.70(d, J=18) 5.07(d, J=5) 5.61(dd, J=5,8) 4.38-4.55(m, 3.92(s)     9.25(d, J=8) 7.47(s) 8.11(d, J=7) 1.90-2.10(m)       Other peak   overlaps with R)   7.51(s) 8.77(d, J=7) 4.38-4.55(m,            obscured        overlaps with H-3')      27 3.38(d, J=17) 5.00(d, J=5) 5.57(dd, J=5,8) 4.25(d, J=14) 3.92(s)     9.28(d, J=8) 7.23(d, J=8) 2.72(s, PyrMe) 1.79(br s)       3.61(d, J=17)   4.45(d, J=14)   7.44-7.48(m) 7.79(s) 1.84(br s)                      3.30-3.70(m)               4.30(br s)      28 3.44-3.74(m) 5.02(s) 5.56(d, J=5,8) 4.42(br s) 3.93(br s) 9.38(d,     J=8) 7.21(dd, J=2,8) 8.05(br s) 2.41(br s)          4.67(br s)   7.41-7.47(m) 8.85(br s) 3.44-3.74(m)               3.93(br s)      29 3.46(d, J=18) 5.08(d, J=5) 5.61-5.65(m) 4.42(br s) 3.91(s) 9.28(d,     J=8) 7.22(d, J=7) 8.04(d, J=5) 4.11(br s)       3.68(d, J=18)      7.43-7.46(m) 8.69(d, J=5) 4.72-4.95(m)      30 3.47(d, J=18) 5.06-5.07(m, 5.81(dd, J=5,8) 4.48(br s) 3.95(s)     9.28(d, J=8) 7.24(dd, J=2,8) 8.74(br s) 1.11(br s)       3.66(d, J=18) overlaps with R)     7.45-7.51(m) 8.07(br s) 1.30(br s)                1.55(br s)               2.25(br s)               2.73(br s)               5.06-5.07(m,               overlaps with H-6)               8.19(br s)      31 3.64(d, J=18) 5.05(br s) 5.56-5.60(m) 4.46(br s) 3.94(s) 9.34(br s)     7.22(dd, J=3,8) 8.71(br s) 8.28(br s)       3.46(d, J=18)      7.43-7.49(m) 8.06(br s) 5.05(br s)               2.79(br s)               2.33(br s)               2.16(br s)               1.59(br s)               1.37(br s)      32 3.49(d, J=17) 5.10(d, J=5) 5.62(dd, J=5,8) 4.44(br s) 3.92(s)     9.29(d, J=8) 7.22(J=8) 8.01(d, J=6) 8.41(br s)       3.67-3.75(m,      7.44-7.48(m) 8.79(d, J=6) 5.25(br s),       overlaps with R)        3.67-3.75(m,               overlaps with H-2),               3.11(br s),               2.35(br s),               2.20(br s),               1.78(br s),               1.49(br s),               1.19(br s)      33 3.45(d, J=17) 5.06(d, J=5) 5.60-5.62(m) 4.31-4.46(m, 3.91-3.95     9.34(d, J=8) 7.23(d, J=8) 8.07-8.11(m, 2.63-2.75(m)       3.62-3.68(m,   overlaps with R) (m,  7.44-7.47(m) overlaps with     3.62-3.68(m,       overlaps with R)    overlaps   R) overlaps with H-2)           with R)   8.90-8.91(m) 3.91-3.95(m,               overlaps with H-7')               4.31-4.46(m,               overlaps with H-3')               5.40(br s)               8.07-8.11(m,               overlaps with SPyrH)      34 3.20-3.50(m) 4.99(d, J=5) 5.47-5.62(m, 4.45(d, J=14) 3.90(s) 9.25(d,     J=8) 7.23(d, J=8) 8.16(m) 1.30(br s)       3.58(d, J=18)  overlaps with R) 4.61(d, J=14)   7.44-7.48(m) 8.76(m)     1.43(br s)               2.26(br s)               3.12(br s)               3.66-3.80(m)               5.47-5.62(m,               overlaps with H-7)               7.48-7.62(m)      35 3.40-3.59(m, 4.98(d, J=5) 5.52(dd, J=5,8) 4.92(d, J=14) 3.90(s)     9.20(d, J=8) 7.23(dd, J=2,8) 8.09(d, J=6) 1.40-1.73(m)       overlaps with R)   4.60(d, J=14)   7.39-7.53(m) 8.53(d, J=6) 2.97-3.16(     m)               4.13-4.26(m)               4.79(s)               5.16-5.40(m)      36 3.47(d, J=18) 5.13(d, J=5) 5.69(dd, J=5,8) 4.29-4.53(m, 3.89(s,     9.28(d, J=8) 7.23(dd, J=2,8) 7.96(d, J=7) 1.16-1.47(m)       3.73(d, J=18)   overlaps with R) overlaps  7.36-7.55(m) 8.68(d, J=7)     1.63-1.95(m)           with R)    3.70-3.92(m)               4.38(br s)      37 3.49(d, J=18) 5.13(d, J=5) 5.69(dd, J=5,8) 4.42-4.57(m) 3.91(s)     9.28(d, J=8) 7.24(dd, J=2,8) 8.03(d, J=7) 1.55-2.13(m)       3.73(d, J=18)      7.37-7.58(m) 8.75(d, J=7) 3.73-4.05(m)               4.38(br s)      38 3.51(d, J=18) 5.14(d, J=5) 5.69(dd, J=5,8) 4.24-4.53(m) 3.91(s)     9.28(d, J=8) 7.23(dd, J=2,8) 8.08(m) 2.92-3.05(m)       3.75(d, J=18)      7.37-7.53(m) 8.62(m) 3.08-3.26(m)               4.24-4.53(m)               5.46(br s)      39 3.51(d, J=18) 5.12(d, J=5) 5.67(dd, J=5,8) 4.26-4.53(m, 3.90(s)     9.26(d, J=8) 7.23(dd, J=2,8) 8.07(d, J=7) 3.11-3.71(m,       3.73(d, J=18)   overlaps with R)   7.37-7.55(m) 8.57(d, J=7) overlaps     with H-2))               4.00-4.50(m,               overlaps with H-3')               5.46(s)               5.65(s)      40 3.47(d, J=17) 5.07(d, J=5) 5.63(dd, J=5,8) 4.38(s) 3.78(s) 9.17(d,     J=8) 7.07(dd, J=7,7) 8.05(d, J=6) 1.60-1.80(m)       3.72(d, J=17)      7.33(d, J=7) 8.78(d, J=6) 3.66(br s)             7.52(d, J=7)  4.37-4.50(m)             7.70(s)      41 3.47(d, J=17) 5.11(d, J=5) 5.64(dd, J=5,8) 4.38(s) 3.76(s) 9.18(d,     J=8) 7.15-7.23(m) 8.04(d, J=6) 1.60-1.80(m)       3.75(d, J=17)      7.23-7.28(m) 8.80(d, J=6) 3.68(br s)             7.42(s)  4.37-4.51(m)      42 3.45(d, J=17) 5.07(d, J=5) 5.62(dd, J=5,8) 4.31-4.44(m) 3.77(s)     9.7(d, J=8) 7.09(dd, J=7,7) 8.06(d, J=6) 1.60-1.80(m)       3.77(d, J=17)      7.34(d, J=7) 8.76(d, J=6) 3.68(br s)             7.52(d, J=7)  4.42-4.54(m)             7.69(s)      43 3.48(d, J=18) 5.13(d, J=5) 5.69(dd, J=5,8) 4.37(s) 3.91(s) 9.28(d,     J=8) 7.24(dd, J=2,8) 8.02(d, J=7) 1.50-1.70(m)       3.74(d, J=18)      7.45-7.48(m) 8.76(d, J=7) 1.80-1.95(m)               4.45(br s)               7.87(d, J=9)      44 3.48(d, J=18) 5.13(d, J=5) 5.69(dd, J=5,8) 4.38(br s) 3.91(s)     9.26(d, J=8) 7.23(dd, J=2,9) 8.01(d, J=7) 1.36(s)       3.74(d, J=18)      7.46(d, J=9) 8.75(d, J=7) 1.40-1.80(m)             7.47(d, J=2)  1.83-1.97(m)               4.42(br s)               7.08(d, J=8)      45 3.43(d, J=17) 5.04(d, J=5) 5.29(dd, J=5,8) 4.43(br s) 3.90(s)     9.24(d, J=8) 7.22(dd, J=2,8) 8.11(d, J=6) 2.42(br s)       3.63(d, J=17)      7.44-7.46(m) 8.83(d, J=6) 2.93(br s)               4.10(br s)               5.43(br s)

We claim:
 1. A compound having the formula ##STR108## wherein Ar is agroup selected from ##STR109## in which R⁴, R⁵ and R⁶ are eachindependently hydrogen, halogen, trihalomethyl, nitro, amino, hydroxy,hydroxy(C₁ -C₆) alkyl, C₁ -C₆ alkyl, --(CH₂)_(n) OR⁷ or --(CH₂)_(n) SR⁷; n is an integer of from 1 to 6; R⁷ is hydrogen or C₁ -C₆ alkyl; R¹ isselected from the group consisting of(a) a C₂ -C₁₀ alkyl groupsubstituted by a carboxyl or sulfonyl group and a group of the formula##STR110## in which R⁹ and R¹⁰ are each independently hydrogen or C₁ -C₆alkyl, said C₂ -C₁₀ alkyl group being optionally interrupted by one ormore nitrogen atoms or carbonyl groups; and (b) a heterocyclic aminoacid group of the formula ##STR111## R² and R³ are each independentlyhydrogen, C₁ -C₆ alkyl or amino(C₁ C₆)alkyl; and R¹¹ is hydrogen, ananionic charge or a carboxyl-protecting group, provided that when R¹¹ ishydrogen or a protecting group, there is also present a counter ion; ora pharmaceutically acceptable salt thereof.
 2. A compound of claim 1wherein Ar is ##STR112## in which R⁴, R⁵ and R⁶ are each independentlyhydrogen, C₁ -C₆ alkyl, halogen, trifluoromethyl, hydroxy, hydroxymethylor amino.
 3. A compound having the formula ##STR113## wherein Ar is agroup selected from ##STR114## in which R⁴, R⁵ and R⁶ are eachindependently hydrogen, halogen, trihalomethyl, nitro, amino, hydroxy,hydroxy (C₁ -C₆) alkyl, (C₁ -C₆) alkyl, --(CH₂)_(n) OR⁷ or --(CH₂)_(n)SR⁷ ; n is an integer of from 1 to 6; R⁷ is hydrogen or C₁ -C₆ alkyl; R¹is a C₂ -C₁₀ alkyl group substituted by a carboxyl or sulfonyl group anda group of the formula ##STR115## in which R⁹ and R¹⁰ are eachindependently hydrogen or C₁ -C₆ alkyl; R² and R³ are each independentlyhydrogen, C₁ -C₆ alkyl or amino (C₁ -C₆) alkyl; and R¹¹ is hydrogen, ananionic charge or a carboxyl-protecting group, provided that when R¹¹ ishydrogen or a protecting group, there is also present a counter ion; ora pharmaceutically acceptable salt thereof.
 4. A compound of claim 3wherein Ar is ##STR116## in which R⁴, R⁵, and R⁶ are each independentlyhydrogen, C₁ -C₆ alkyl, halogen, trifluoromethyl, hydroxy, hydroxymethylor amino.
 5. A compound having the formula ##STR117## wherein Ar is agroup selected from ##STR118## in which R⁴, R⁵ and R⁶ are eachindependently hydrogen, halogen, trihalomethyl, nitro, amino, hydroxy,hydroxy(C₁ -C₆) alkyl, C₁ -C₆ alkyl, --(CH₂)_(n) OR⁷ or --(CH₂)_(n) SR⁷; n is an integer of from 1 to 6; R⁷ is hydrogen or C₁ -C₆ alkyl; R¹ isselected from the group consisting of ##STR119## wherein R⁸ is NR⁹ R¹⁰or ##STR120## in which R⁹ and R¹⁰ are each independently hydrogen or C₁-C₆ alkyl; m is 0 or 1; n is as defined above; o is 0 or an integer offrom 1 to 4; p is 0 or 1; q is 0 or 1, with the proviso that q is 0 onlywhen p is 0; r and s each represent an integer of from 1 to 4; R¹² is C₁-C₆ alkyl; R² and R³ are each independently hydrogen, C₁ -C₆ alkyl oramino(C₁ -C₆)alkyl; and R¹¹ is hydrogen, an anionic charge or acarboxyl-protecting group, provided that when R¹¹ is hydrogen or aprotecting group, there is also present a counter ion; or apharmaceutically acceptable salt thereof.
 6. A compound having theformula ##STR121## wherein Ar is a group selected from ##STR122## inwhich R⁴, R⁵ and R⁶ are each independently hydrogen, halogen,trihalomethyl, nitro, amino, hydroxy, hydroxy(C₁ -C₆)alkyl, --(CH₂)_(n)OR⁷ or --(CH₂)_(n) SR⁷ ; n is an integer of from 1 to 6; R⁷ is hydrogenor C₁ -C₆ alkyl; R¹ is ##STR123## wherein R⁸ is NR⁹ R¹⁰ or ##STR124## inwhich R⁹ and R¹⁰ are each independently hydrogen or C₁ -C₆ alkyl; m is 0or 1; n is as defined above; o is 0 or an integer of from 1 to 4; p is 0or 1; q is 0 or 1, with the proviso that q is 0 only when p is 0; R² andR³ are each independently hydrogen, C₁ -C₆ alkyl or amino(C₁ -C₆)alkyl;and R¹¹ is hydrogen, an anionic charge or a carboxyl-protecting group,provided that when R¹¹ is hydrogen or a protecting group, there is alsopresent a counter ion; or a pharmaceutically acceptable salt thereof. 7.A compound having the formula ##STR125## wherein Ar is a group selectedfrom ##STR126## in which R⁴, R⁵ and R⁶ are each independently hydrogen,halogen, trihalomethyl, nitro, amino, hydroxy, hydroxy(C₁ -C₆) alkyl, C₁-C₆ alkyl, --(CH₂)_(n) OR⁷ or --(CH₂)_(n) SR⁷ ; n is an integer of from1 to 6; R⁷ is hydrogen or C₁ -C₆ alkyl; R¹ is ##STR127## wherein R⁸ isNR⁹ R¹⁰ or ##STR128## in which R⁹ and R¹⁰ are each independentlyhydrogen or C₁ -C₆ alkyl; r and s each represent an integer of from 1 to4; R² and R³ are each independently hydrogen, C₁ -C₆ alkyl or amino(C₁-C₆)alkyl; and R¹¹ is hydrogen, an anionic charge or acarboxyl-protecting group, provided that when R¹¹ is hydrogen or aprotecting group, there is also present a counter ion; or apharmaceutically acceptable salt thereof.
 8. A compound having theformula ##STR129## wherein Ar is a group selected from ##STR130## inwhich R⁴, R⁵ and R⁶ are each independently hydrogen, halogen,trihalomethyl, nitro, amino, hydroxy, hydroxy(C₁ -C₆) alkyl, C₁ -C₆alkyl, --(CH₂)_(n) OR⁷ or --(CH₂)_(n) SR⁷ ; n is an integer of from 1 to6; R⁷ is hydrogen or C₁ -C₆ alkyl; R¹ is ##STR131##
 9. A compound havingthe formula ##STR132## wherein Ar is a group selected from ##STR133## inwhich R⁴, R⁵ and R⁶ are each independently hydrogen, halogen,trihalomethyl, nitro, amino, hydroxy, hydroxy(C₁ -C₆) alkyl, C₁ -C₆alkyl, --(CH₂)_(n) OR⁷ or --(CH₂)_(n) SR⁷ ; n is an integer of from 1 to6; R⁷ is hydrogen or C₁ -C₆ alkyl; R¹ is ##STR134## wherein R⁸ is NR⁹R¹⁰ or ##STR135## in which R⁹ and R¹⁰ are each independently hydrogen orC₁ -C₆ alkyl; m is 0 or 1; n is as defined above; R² and R³ are eachindependently hydrogen, C₁ -C₆ alkyl or amino(C₁ -C₆)alkyl; R¹² is C₁-C₆ alkyl; and R¹¹ is hydrogen, an anionic charge or acarboxyl-protecting group, provided that when R¹¹ is hydrogen or aprotecting group, there is also present a counter ion; or apharmaceutically acceptable salt thereof.
 10. A compound selected fromthe group consistingof1-[(5S)-5-Amino-5-carboxy-1-pentyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(5S)-5-Amino-5-carboxy-1-pentyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(±)-5-Amino-5-carboxy-1-hexyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-tris-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3,5-dichloro-4-hydroxyphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-chloro-5-trifluoromethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3,5-dichloro-4-aminophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dimethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-hydroxymethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-fluorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof (compound ofExample 17)1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-chloro-5-trifluoromethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,3-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2-ethyl-4-[[(6R)-trans-2-carboxy-8oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2-methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2-(3-aminopropyl)-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4R)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4R)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-hydroxymethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4R)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(3S)-3-Amino-3-carboxy-1-propyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(2R)-2-Amino-2-carboxy-1-ethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(2S)-5-Amino-2-carboxy-1-pentyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(2S)-4-Amino-2-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-phenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(2S)-4-Guanidino-2-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof 1-[(2S,4R)-2-Carboxypyrrolidin-4-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(1S)-1-(3-Amino-1-propyl)-N-(carboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(1S)-1-(3-Guanidino-1-propyl)-N-(carboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-((1S)-1-Carboxy-4-guanidino-1-butyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(5S)-5-Amino-5-(N-carboxymethyl)carbamoyl-1-pentyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-(N-carboxymethyl)carbamoyl-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-(Carboxymethyl)-N-(2-amino-1-ethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-(Carboxymethyl)-N-(3-amino-1-propyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-(Carboxymethyl)-N-(2-guanidino-1-ethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-iodophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-chlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4R)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-iodophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Guanidino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-(t-Butoxycarbonylamino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-iodophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof; and 1-[(2S,4S)-2-Carboxypyrrolidin-4-yl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof.
 11. A compoundselected from the group consistingof1-[(5S)-5-Amino-5-carboxy-1-pentyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(5S)-5-Amino-5-carboxy-1-pentyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(±)-5-Amino-5-carboxy-1-hexyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-chloro-5-trifluoromethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3,5-dichloro-4-aminophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4-yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-hydroxymethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-chloro-5-trifluoromethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,3-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2-ethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2-methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2-(3-aminopropyl)-4-[[(6R-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4R)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4R)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-hydroxymethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4R)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(2S)-5-Amino-2-carboxy-1-pentyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(2S)-4-Amino-2-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(2S)-4-Guanidino-2-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof 1-[(2R,4S)-4-carboxy-2-pyrrolidinyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(1S)-1-(3-Amino-1-propyl)-N-(carboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(1S)-1-(3-Guanidino-1-propyl)-N-(carboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-((1S)-1-carboxy-4-guanidino-1-butyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(5S)-5-Amino-5-(N-carboxymethyl)carbamoyl-1-pentyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-(N-carboxymethyl)carbamoyl-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-(Carboxymethyl)-N-(2-amino-1-ethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-(Carboxymethyl)-N-(3-amino-1-propyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof; and1-[(4S)-4-Guanidino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof.
 12. A compoundselected from the group consistingof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,6-dichloropyridin-4yl)thioacetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(3-bromophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2-chloro-5-trifluoromethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,6-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,4,5-trichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2,3-dimethyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4S)-4-Amino-4-carboxy-1-butyl]-2-methyl-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4R)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(4R)-4-Amino-4-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichloro-4-hydroxymethylphenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(2S)-4-Amino-2-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(2S)-4-Guanidino-2-carboxy-1-butyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(1S)-1-(3-Amino-1-propyl)-N-(carboxymethyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[N-((1S)-1-carboxy-4-guanidino-1-butyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof1-[(5S)-5-Amino-5-(N-carboxymethyl)carbamoyl-1-pentyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof; and1-[N-(Carboxymethyl)-N-(3-amino-1-propyl)carbamoylmethyl]-4-[[(6R)-trans-2-carboxy-8-oxo-7-[(2,5-dichlorophenylthio)acetamido]-5-thia-1-azabicyclo[4.2.0]-oct-2-en-3-yl]methylthio]pyridiniuminner salt or a pharmaceutically acceptable salt thereof.
 13. A compoundof the formula ##STR136## wherein R¹¹ is hydrogen, an anionic charge ora carboxyl-protecting group, provided that when R¹¹ is hydrogen or aprotecting group, there is also present a counter ion; or apharmaceutically acceptable salt thereof.
 14. The compound of claim 11wherein R¹¹ is hydrogen, or a pharmaceutically acceptable salt thereof.15. A pharmaceutical compostion comprising an effective antibacterialamount of a compound of claim 1 and a pharmaceutically acceptablecarrier or diluent.
 16. A method of treating a bacterial infection whichcomprises administering to a host afflicted with such infection aneffective antibacterial amount of a compound of claim
 1. 17. A method oftreating a bacterial infection caused by a strain ofmethicillin-resistant Staphylococcus aureus which comprisesadministering to a host afflicted with such infection an effectiveantibacterial amount of a compound of claim 1.